Search

Background: Patients with COPD are at high risk of lung cancer developing, but no validated predictive biomarkers have been reported to identify these patients. Molecular profiling of exhaled breath by electronic nose (eNose) technology may qualify for early detection of lung cancer in patients with COPD., Research Question: Can eNose technology be used for prospective detection of early lung cancer in patients with COPD?, Study Design and Methods: BreathCloud is a real-world multicenter prospective follow-up study using diagnostic and monitoring visits in day-to-day clinical care of patients with a standardized diagnosis of asthma, COPD, or lung cancer. Breath profiles were collected at inclusion in duplicate by a metal-oxide semiconductor eNose positioned at the rear end of a pneumotachograph (SpiroNose; Breathomix). All patients with COPD were managed according to standard clinical care, and the incidence of clinically diagnosed lung cancer was prospectively monitored for 2 years. Data analysis involved advanced signal processing, ambient air correction, and statistics based on principal component (PC) analysis, linear discriminant analysis, and receiver operating characteristic analysis., Results: Exhaled breath data from 682 patients with COPD and 211 patients with lung cancer were available. Thirty-seven patients with COPD (5.4%) demonstrated clinically manifest lung cancer within 2 years after inclusion. Principal components 1, 2, and 3 were significantly different between patients with COPD and those with lung cancer in both training and validation sets with areas under the receiver operating characteristic curve of 0.89 (95% CI, 0.83-0.95) and 0.86 (95% CI, 0.81-0.89). The same three PCs showed significant differences (P < .01) at baseline between patients with COPD who did and did not subsequently demonstrate lung cancer within 2 years, with a cross-validation value of 87% and an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.84-0.95)., Interpretation: Exhaled breath analysis by eNose identified patients with COPD in whom lung cancer became clinically manifest within 2 years after inclusion. These results show that eNose assessment may detect early stages of lung cancer in patients with COPD., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Growing evidence indicates high comorbid anxiety and depression in patients with asthma. However, the mechanisms underlying this comorbid condition remain unclear. The aim of this study was to investigate the role of inflammation in comorbid anxiety and depression in three asthma patient cohorts of the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) project., Methods: U-BIOPRED was conducted by a European Union consortium of 16 academic institutions in 11 European countries. A subset dataset from subjects with valid anxiety and depression measures and a large blood biomarker dataset were analysed, including 198 non-smoking patients with severe asthma (SAn), 65 smoking patients with severe asthma (SAs), 61 non-smoking patients with mild-to-moderate asthma (MMA), and 20 healthy non-smokers (HC). The Hospital Anxiety and Depression Scale was used to measure anxiety and depression and a series of inflammatory markers were analysed by the SomaScan v3 platform (SomaLogic, Boulder, Colo). ANOVA and the Kruskal-Wallis test were used for multiple-group comparisons as appropriate., Results: There were significant group effects on anxiety and depression among the four cohort groups (p < 0.05). Anxiety and depression of SAn and SAs groups were significantly higher than that of MMA and HC groups (p < 0.05. There were significant differences in serum IL6, MCP1, CCL18, CCL17, IL8, and Eotaxin among the four groups (p < 0.05). Depression was significantly associated with IL6, MCP1, CCL18 level, and CCL17; whereas anxiety was associated with CCL17 only (p < 0.05)., Conclusions: The current study suggests that severe asthma patients are associated with higher levels of anxiety and depression, and inflammatory responses may underlie this comorbid condition., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Professor Hou sits on the ECNP Scientific Advisory Panel and currently holds a grant from Asthma Allergy Inflammation Research charity. Prof. Shaw receives consulting fees from Adherium, Nuvoair, Astra Zeneca and Chiesi. He also receives honoraria from Astra Zeneca and Chiesi and travel support from Chiesi and GSK. Professor Sven-Eric Dahlén declares consulting fees from Astra Zenica, Cayman Chemicals, GSK, Novartis, Regeneron, Sanofi and Teva and honorarium from Sanofi. Dr Barbro Dahlén is in receipt of grants from GSK and Novartis and declares consulting fees from Novartis, Astra Zeneca and Sanofi. She is on the advisory board for Astra Zeneca and Sanofi. Prof. Fowler receives a grant from Boehringer Ingelheim and an honorarium from Chiesi. Prof. Sandstrom received payment for the Boehringer Ingelheim lecture (paid to his institution). Dr Auffrey and Dr De Meulder have both received support for the manuscript from the Innovative Medicines Initiative. Prof. Adcock has received grants from GSK, MRC and EPSRC. He also declares consulting fees from GSK, Sanofi, Chiesi and Kinaset. He has received honoraria from Astra Zeneca, Sanofi, Eurodrug, and Sunovion. He has also received payment for expert testimony from Chiesi and travel support from Astra Zeneca. Prof. Chung is in receipt of grants from MRC, EPSRC and GSK and honoraria from Astra Zeneca and Novartis. He is on the advisory board of Astra Zeneca, GSK, Roche and Novartis. Prof. Sterk received a grant from Innovative Medicines Initiative and has a non-substantial interest in SME Breathomix. Prof. Skipp has a grant from EU UBIOPRED IMI FP and is a shareholder in TopMD Precision Medicine Ltd. Prof. Djukanovic receives consulting fees from Synairgen and honoraria from Regeneron, GSK and is on the advisory board for Synairgen. He also holds stock in Synairgen. Dr Ye, Dr Cheng, Dr Bakke, Dr Caruso, Dr Horvárth, Prof. Howarth, Dr Krug, Dr Montuschi, Dr Sanak and Dr Schofield report no potential conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pseudomonas aeruginosa (PA) is an important respiratory pathogen for cystic fibrosis (CF) patients. Routine microbiology surveillance is time-consuming, and is best performed on expectorated sputum. As alternative, volatile organic compounds (VOCs) may be indicative of PA colonisation. In this study, we aimed to identify VOCs associated with PA in literature and perform targeted exhaled breath analysis to recognize PA positive CF patients non-invasively., Methods: This study consisted of 1) a literature review to select VOCs of interest, and 2) a cross-sectional CF study. Definitions used: A) PA positive, PA culture at visit/chronically; B) PA free, no PA culture in ≥12 months. Exhaled VOCs were identified via quadrupole MS. The primary endpoint was the area under the receiver operating characteristics curve (AUROCC) of individual VOCs as well as combined VOCs against PA culture., Results: 241 VOCs were identified in literature, of which 56 were further evaluated, and 13 could be detected in exhaled breath in our cohort. Exhaled breath of 25 pediatric and 28 adult CF patients, PA positive (n=16) and free (n=28) was available. 3/13 VOCs were significantly (p<0.05) different between PA groups in children; none were in adults. Notably, a composite model based on 5 or 1 VOC(s) showed an AUROCC of 0.86 (CI 0.71-1.0) and 0.87 (CI 0.72-1.0) for adults and children, respectively., Conclusions: Targeted VOC analysis appears to discriminate children and adults with and without PA positive cultures with clinically acceptable sensitivity values., Competing Interests: Declaration of Competing Interests AHM and PB are supported by an innovation grant from Vertex Pharmaceuticals B.V. PJS is scientific advisor and has a formally inconsiderable interest in the SME Breathomix AHM reports grants and personal fees from GSK, Boehringer Ingelheim, and AstraZeneca, and grants from Chiesi, outside the submitted work., (Copyright © 2021. Published by Elsevier B.V.)

Background: Although estimates of suboptimal adherence to oral corticosteroids in asthma range from 30% to 50%, no ideal method for measurement exists; the impact of poor adherence in severe asthma is likely to be particularly high., Research Questions: What is the prevalence of suboptimal adherence detected by self-reporting and direct measures? Is suboptimal adherence associated with disease activity?, Study Design and Methods: Data were included from individuals with severe asthma taking part in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes) study and prescribed daily oral corticosteroids. Participants completed the Medication Adherence Report Scale, a five-item questionnaire used to grade adherence on a scale from 1 to 5, and provided a urine sample for analysis of prednisolone and metabolites by liquid chromatography-mass spectrometry., Results: Data from 166 participants were included in this study: mean (SD) age, 54.2 (± 11.9) years; FEV 1 , 65.1% (± 20.5%) predicted; female, 58%; 37% completing the Medication Adherence Report Scale reported suboptimal adherence; and 43% with urinary corticosteroid data did not have detectable prednisolone or metabolites in their urine. Good adherence by both methods was detected in 49 of the 142 (35%) of participants in whom both methods were performed; adherence detection did not match between methods in 53%. Self-reported high adherers had better asthma control and quality of life, whereas directly measured high adherers had lower blood eosinophil levels., Interpretation: Low adherence is a common problem in severe asthma, whether measured directly or self-reported. We report poor agreement between the two methods, suggesting some disassociation between self-assessment of medication adherence and regular oral corticosteroid use, which suggests that each approach may provide complementary information in clinical practice., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: Asthma prevalence is 339 million globally. 'Severe asthma' (SA) comprises subjects with uncontrolled asthma despite proper management., Objectives: To compare asthma from diverse ethnicities and environments., Methods: A cross-sectional analysis of two adult cohorts, a Brazilian (ProAR) and a European (U-BIOPRED). U-BIOPRED comprised of 311 non-smoking with Severe Asthma (SAn), 110 smokers or ex-smokers with SA (SAs) and 88 mild to moderate asthmatics (MMA) while ProAR included 544 SA and 452 MMA. Although these projects were independent, there were similarities in objectives and methodology, with ProAR adopting operating procedures of U-BIOPRED., Results: Among SA subjects, age, weight, proportion of former smokers and FEV 1 pre-bronchodilator were similar. The proportion of SA with a positive skin prick tests (SPT) to aeroallergens, the scores of sino-nasal symptoms and quality of life were comparable. In addition, blood eosinophil counts (EOS) and the % of subjects with EOS > 300 cells/μl were not different. The Europeans with SA however, were more severe with a greater proportion of continuous oral corticosteroids (OCS), worse symptoms and more frequent exacerbations. FEV 1 /FVC pre- and post-bronchodilator were lower among the Europeans. The MMA cohorts were less comparable in control and treatment, but similar in the proportion of allergic rhinitis, gastroesophageal reflux disease and EOS >3%., Conclusions: ProAR and U-BIOPRED cohorts, with varying severity, ethnicity and environment have similarities, which provide the basis for global external validation of asthma phenotypes. This should stimulate collaboration between asthma consortia with the aim of understanding SA, which will lead to better management., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated., Methods: Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control. The study assessed various immune, inflammatory, and oxidative stress parameters, as well as markers of eosinophil and neutrophil activity, in exhaled breath condensate, plasma, and sputum collected at three phases (baseline, during loss of control, and following recovery)., Results: Loss of asthma control was characterized by increased sputum eosinophils, whereas no differences were detected between the three phases for most inflammatory and oxidative stress responses. There were also no differences detected for markers of activated eosinophils (eosinophil cationic protein and bromotyrosine) and neutrophils (myeloperoxidase and chlorotyrosine). However, free eosinophilic granules and citrullinated histone H 3 , suggestive of eosinophil cytolysis and potentially eosinophil extracellular trap formation, were enhanced. Baseline blood eosinophils and changes in asymmetric dimethylarginine (an inhibitor of nitric oxide synthase) in plasma were found to correlate with the decrease in FEV 1 percent predicted upon ICS withdrawal (both, r s  = 0.46; P = .03)., Conclusions: The clinical effect in mild to moderate asthma upon interruption of ICS therapy is not related to the classic inflammatory activation of eosinophils and neutrophils. It may, however, reflect another pathway underlying the onset of loss of disease control and asthma exacerbations., Trial Registry: The Netherlands Trial Register; No.: NTR3316; URL: trialregister.nl/trial/3172., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma., Methods: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10 -6 in stage 1. We set genome-wide significance at p less than 5 × 10 -8 . For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls., Findings: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10 -10 ), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10 -8 ), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10 -9 ). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10 -5 ) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022)., Interpretation: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population., Funding: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Antibiotics do not reduce mortality or short-term treatment non-response in patients receiving treatment for acute exacerbations of COPD in an outpatient setting. However, the long-term effects of antibiotics are unknown. The aim of this study was to investigate if the antibiotic doxycycline added to the oral corticosteroid prednisolone prolongs time to next exacerbation in patients with COPD receiving treatment for an exacerbation in the outpatient setting., Methods: In this randomised double-blind placebo-controlled trial, we recruited a cohort of patients with COPD from outpatient clinics of nine teaching hospitals and three primary care centres in the Netherlands. Inclusion criteria were an age of at least 45 years, a smoking history of at least 10 pack-years, mild-to-severe COPD (Global Initiative of Chronic Obstructive Lung Disease [GOLD] stage 1-3), and at least one exacerbation during the past 3 years. Exclusion criteria were poor mastery of the Dutch language, poor cognitive functioning, known allergy to doxycycline, pregnancy, and a life expectancy of shorter than 1 month. If a participant had an exacerbation, we randomly assigned them (1:1; with permuted blocks of variable sizes [ranging from two to ten]; stratified by GOLD stage 1-2 vs 3) to a 7 day course of oral doxycycline 100 mg daily (200 mg on the first day) or placebo. Exclusion criteria for randomisation were fever, admission to hospital, and current use of antibiotics or use within the previous 3 weeks. Patients in both groups received a 10 day course of 30 mg oral prednisolone daily. Patients, investigators, and those assessing outcomes were masked to treatment assignment. The primary outcome was time to next exacerbation in all randomly allocated patients except for those incorrectly randomly allocated who did not meet the inclusion criteria or met the exclusion criteria. This trial is registered with the Netherlands Trial Register, number NTR2499., Findings: Between Dec 22, 2010, and Aug 6, 2013, we randomly allocated 305 (34%) patients from the cohort of 887 patients to doxycycline (152 [50%]) or placebo (153 [50%]), excluding four (1%) patients (two [1%] from each group) who were incorrectly randomly allocated from the analysis. 257 (85%) of 301 patients had a next exacerbation (131 [87%] of 150 in the doxycycline group vs 126 [83%] of 151 in the placebo group). Median time to next exacerbation was 148 days (95% CI 95-200) in the doxycycline group compared with 161 days (118-211) in the placebo group (hazard ratio 1·01 [95% CI 0·79-1·31]; p=0·91). We did not note any significant differences between groups in the frequency of adverse events during the first 2 weeks after randomisation (47 [31%] of 150 in the doxycycline group vs 53 [35%] of 151 in the placebo group; p=0·54) or in serious adverse events during the 2 years of follow-up (42 [28%] vs 43 [29%]; p=1)., Interpretation: In patients with mild-to-severe COPD receiving treatment for an exacerbation in an outpatient setting, the antibiotic doxycycline added to the oral corticosteroid prednisolone did not prolong time to next exacerbation compared with prednisolone alone. These findings do not support prescription of antibiotics for COPD exacerbations in an outpatient setting., Funding: Netherlands Organization for Health Research and Development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

Background: Eosinophilic airway inflammation is associated with increased corticosteroid responsiveness in asthma, but direct airway sampling methods are invasive or laborious. Minimally invasive markers for airway eosinophilia could present an alternative method, but estimates of their accuracy vary., Methods: We did a systematic review and searched Medline, Embase, and PubMed for studies assessing the diagnostic accuracy of markers against a reference standard of induced sputum, bronchoalveolar lavage, or endobronchial biopsy in patients with asthma or suspected asthma (for inception to Aug 1, 2014). Unpublished results were obtained by contacting authors of studies that did not report on diagnostic accuracy, but had data from which estimates could be calculated. We assessed risk of bias with QUADAS-2. We used meta-analysis to produce summary estimates of accuracy., Findings: We included 32 studies: 24 in adults and eight in children. Of these, 26 (81%) showed risk of bias in at least one domain. In adults, three markers had extensively been investigated: fraction of exhaled nitric oxide (FeNO) (17 studies; 3216 patients; summary area under the receiver operator curve [AUC] 0·75 [95% CI 0·72-0·78]); blood eosinophils (14 studies; 2405 patients; 0·78 [0·74-0·82]); total IgE (seven studies; 942 patients; 0·65 [0·61-0·69]). In children, only FeNO (six studies; 349 patients; summary AUC 0·81 [0·72-0·89]) and blood eosinophils (three studies; 192 patients; 0·78 [0·71-0·85]) had been investigated in more than one study. Induced sputum was most frequently used as the reference standard. Summary estimates of sensitivity and specificity in detecting sputum eosinophils of 3% or more in adults were: 0·66 (0·57-0·75) and 0·76 (0·65-0·85) for FeNO; 0·71 (0·65-0·76) and 0·77 (0·70-0·83) for blood eosinophils; and 0·64 (0·42-0·81) and 0·71 (0·42-0·89) for IgE., Interpretation: FeNO, blood eosinophils, and IgE have moderate diagnostic accuracy. Their use as a single surrogate marker for airway eosinophilia in patients with asthma will lead to a substantial number of false positives or false negatives., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Anxiety and depression are prevalent in patients with asthma, and associated with more exacerbations and increased health care utilization. Since psychiatric intervention might improve asthma control, we examined whether patients with severe, prednisone-dependent asthma are at higher risk of these disorders than patients with severe non-prednisone dependent asthma or mild-moderate asthma, and whether they exhibit different personality traits., Methods: Sixty-seven adults with severe prednisone-dependent asthma, 47 with severe non-prednisone dependent and 73 patients with mild-moderate asthma completed the HADS depression and anxiety subscale and the NEO-FFI for personality traits. In addition, asthma duration, body mass index and FEV1 were measured., Results: The prevalence of clinically significant depressive symptoms (9% vs. 0 vs. 0%; p = 0.009) and anxiety symptoms (19% vs. 6.4 vs. 5.5%; p = 0.01), was higher in patients with severe, prednisone-dependent asthma than in patients with severe non-prednisone dependent or mild-moderate asthma. Patients with prednisone-dependent asthma were respectively 3.4 (95%CI: 1.0-10.8 p = 0.04) and 3.5 (95%CI: 1.3-9.6 p = 0.01) times more likely to have significant depression symptoms and 1.6 (95%CI: 0.7-3.7, p = 0.2) and 2.5 (95%CI: 01.1-5.5, p = 0.02) times more likely to have symptoms of anxiety than patients with severe non-prednisone dependent or mild-moderate asthma. There were no differences found in personality traits between the 3 groups., Conclusion: Patients with severe, prednisone-dependent asthma have more often psychological distress as compared to patients with severe non-prednisone dependent or mild-moderate asthma., (Copyright © 2014. Published by Elsevier Ltd.)

Introduction: Children with persistent asthma may have diminished lung function in early adulthood. In our previous study ('CATO') we showed preservation of lung function in asthmatic children, during 2 years of treatment that was guided by airway hyperresponsiveness (AHR). The aim of the present prospective follow up study was to investigate whether the positive effect of the AHR strategy on lung function had persisted beyond the duration of the intervention study, after several years of usual care by paediatrician and general practitioner., Methods: With a mean interval of 4.4 y after the last visit, 137 subjects (67% of the original CATO population) participated in this follow-up study. Evaluation consisted of spirometry (n = 137), a methacholine challenge test (n = 83), data on inhaled steroid treatment and asthma exacerbations (n = 137), and an asthma symptom diary during 6 weeks (n = 90)., Results: At follow-up, lung function, % symptom-free days and exacerbation rates of both treatment strategy groups was similar. The mean dose of inhaled corticosteroids had diminished from 550 μg/day at the end of CATO to 235 μg/day at follow-up. The decrease in AHR measured at the end of CATO was maintained at follow-up for both treatment strategy groups., Conclusion: The beneficial effect on lung function of 2 years treatment guided by AHR was lost after 3-7 years of usual care. This suggests that an AHR-guided treatment strategy may need to be sustained in order to preserve lung function., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Sarcoidosis is a systemic granulomatous disease of unknown cause that affects the lungs in over 90% of cases. Breath analysis by electronic nose technology provides exhaled molecular profiles that have potential in the diagnosis of several respiratory diseases., Objectives: We hypothesized that exhaled molecular profiling may distinguish well-characterized patients with sarcoidosis from controls. To that end we performed electronic nose measurements in untreated and treated sarcoidosis patients and in healthy controls., Methods: 31 sarcoidosis patients (11 patients with untreated pulmonary sarcoidosis [age: 48.4 ± 9.0], 20 patients with treated pulmonary sarcoidosis [age: 49.7 ± 7.9]) and 25 healthy controls (age: 39.6 ± 14.1) participated in a cross-sectional study. Exhaled breath was collected twice using a Tedlar bag by a standardized method. Both bags were then sampled by an electronic nose (Cyranose C320), resulting in duplicate data. Statistical analysis on sensor responses was performed off-line by principal components (PC) analyses, discriminant analysis and ROC curves., Results: Breathprints from patients with untreated pulmonary sarcoidosis were discriminated from healthy controls (CVA: 83.3%; AUC 0.825). Repeated measurements confirmed those results. Patients with untreated and treated sarcoidosis could be less well discriminated (CVA 74.2%), whereas the treated sarcoidosis group was undistinguishable from controls (CVA 66.7%), Conclusion: Untreated patients with active sarcoidosis can be discriminated from healthy controls. This suggests that exhaled breath analysis has potential for diagnosis and/or monitoring of sarcoidosis., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Smoking in asthma occurs frequently and is associated with increased symptom severity, an impaired response to corticosteroids, and accelerated lung function decline. Airway pathology in smoking asthmatics is characterized by neutrophilia and epithelial changes such as goblet cell hyperplasia and increased proliferation. Bronchial CD8(+) T cells are implicated in lung function decline in asthma and COPD. We hypothesized that smoking modifies airway inflammation in asthma by increasing the number of CD8(+) T cells at an early stage., Objectives & Methods: To study effects of smoking on airway pathology in bronchial biopsies from atopic patients with controlled intermittent or mild persistent asthma (12 smokers, 9.7 py and 11 never-smokers, 0.0 py; 20-50 yrs; FEV1 > 70% predicted; PC20MCh < 8 mg/mL, no ICS) using immunohistochemistry., Results: Smoking asthmatics showed higher numbers of bronchial CD8(+) T cells (55.8 vs 23.9 cells/0.1 mm(2); p = 0.001) and CD68(+) macrophages (7.5 vs 4.6 cells/0.1 mm(2), p = 0.012), and a lower CD4(+)/CD8(+) cell ratio (0.16 vs 0.40; p = 0.007) compared with non-smoking asthmatics, but no difference in neutrophils. Furthermore, the % intact epithelium was higher in smoking asthmatics (49.3 vs 23.3, p = 0.001)., Conclusion: Smoking asthmatics with a limited smoking history show a distinct pattern of airway pathology characterized by a bronchial infiltrate of CD8(+) T cells and CD68(+) macrophages, and epithelial remodelling resembling COPD-like features. This raises the hypothesis that early presence of CD8(+) T cells contributes to disease progression in smoking asthmatics., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Chronic inflammatory pulmonary diseases such as COPD and asthma are highly prevalent and associated with a major health burden worldwide. Despite a wealth of biologic and clinical information on normal and pathologic airway structure and function, the primary causes and mechanisms of disease remain to a large extent unknown, preventing the development of more efficient diagnosis and treatment. We propose to overcome these limitations through an integrative systems biology research strategy designed to identify the functional and regulatory pathways that play central roles in respiratory pathophysiology, starting with severe asthma. This approach relies on global genome, transcriptome, proteome, and metabolome data sets collected in cross-sectional patient cohorts with high-throughput measurement platforms and integrated with biologic and clinical data to inform predictive multiscale models ranging from the molecular to the organ levels. Working hypotheses formulated on the mechanisms and pathways involved in various disease states are tested through perturbation experiments using model simulation combined with targeted and global technologies in cellular and animal models. The responses observed are compared with those predicted by the initial models, which are refined to account better for the results. Novel perturbation experiments are designed and tested both computationally and experimentally to arbitrate between competing hypotheses. The process is iterated until the derived knowledge allows a better classification and subphenotyping of severe asthma using complex biomarkers, which will facilitate the development of novel diagnostic and therapeutic interventions targeting multiple components of the molecular and cellular pathways involved. This can be tested and validated in prospective clinical trials.

Background: Internet and short message service are emerging tools for chronic disease management in adolescents, but few data exist on the barriers to and benefits of internet-based asthma self-management. Our objective was to reveal the barriers and benefits perceived by adolescents with well-controlled and poorly controlled asthma to current and internet-based asthma management., Methods: Ninety-seven adolescents with mild-to-moderate persistent asthma monitored their asthma control on a designated Web site. After 4 weeks, 35 adolescents participated in eight focus groups. Participants were stratified in terms of age, gender, and asthma control level. We used qualitative and quantitative methods to analyze the written focus group transcripts., Results: Limited self-efficacy to control asthma was a significant barrier to current asthma management in adolescents with poor asthma control (65%) compared to adolescents with good asthma control (17%; p < 0.01). The former group revealed the following several benefits from internet-based asthma self-management: feasible electronic monitoring; easily accessible information; e-mail communication; and use of an electronic action plan. Personal benefits included the ability to react to change and to optimize asthma control. Patients with poor asthma control were able and ready to incorporate internet-based asthma self-management for a long period of time (65%), whereas patients with good control were not (11%; p < 0.01)., Conclusions: Our findings reveal a need for the support of self-management in adolescents with poorly controlled asthma that can be met by the application of novel information and communication technologies. Internet-based self-management should therefore target adolescents with poor asthma control.

Background: The single-breath N(2) test (sbN(2)-test) is closely related to small airways pathology in resected lung specimens of smokers. We investigated whether uneven ventilation and airway closure are associated with specific markers of airway inflammation as obtained by bronchial biopsies, BAL, and induced sputum in patients with manifest COPD., Methods: Fifty-one patients with stable COPD not receiving corticosteroids were examined in a cross-sectional study (43 men; mean [SD] age, 63 +/- 8 years; exsmokers and smokers; median pack-years, 41 [interquartile range, 31 to 51 pack-years]). Postbronchodilator spirometry (FEV(1), 63 +/- 8% of predicted) and sbN(2)-test (slope of phase III [DeltaN(2)], closing capacity [CC]/total lung capacity [TLC] percentage of predicted) were performed. Inflammatory cell counts were assessed in bronchial biopsies, BAL (only in the first half of patients), and induced sputum. Neutrophil elastase (NE), secretory leukocyte proteinase inhibitor (SLPI), and interleukin-8 levels were determined in BAL fluid., Results: DeltaN(2) increased with subepithelial neutrophil numbers in bronchial biopsies (rs = 0.337, p = 0.017) and with NE levels (rs = 0.443, p = 0.039), NE/neutrophil ratio (rs = 0.575, p = 0.005) and SLPI levels (rs = 0.484, p = 0.022) in BAL. CC/TLC was associated with BAL neutrophil numbers (rs = 0.448, p = 0.048). The sbN(2)-test was not associated with any other inflammatory cell type in BAL or biopsies, nor with inflammatory cell counts in sputum. Of importance, the correlations between DeltaN(2) and BAL NE/neutrophil ratio, and between CC/TLC and BAL neutrophil numbers remained significant when adjusting for FEV(1) percentage of predicted., Conclusions: The results of the sbN(2)-test are associated with neutrophilic inflammation in bronchial biopsies and BAL in patients with COPD. Our findings support a role of neutrophilic inflammation in the pathogenesis of small airways dysfunction in COPD.

Background: Bronchodilation following deep inspiration is usually impaired in patients with asthma. This might be due to changes in airway mechanics in the presence of inflammation or structural changes within the airways. Although inhaled corticosteroid treatment has been shown to improve airway responses to deep inspiration in patients with asthma, airway inflammation can persist despite inhaled corticosteroid treatment, and thus could still influence the airway mechanics during deep breaths. We hypothesized that oral steroid treatment further optimizes deep inspiration-induced bronchodilation in clinically stable asthmatic patients who are receiving therapy with inhaled corticosteroids., Methods: Twenty-four atopic patients with mild-to-moderate persistent asthma (FEV1, > 70% predicted; provocative concentration of methacholine causing a 20% fall in FEV1 [PC20], < 8 mg/mL), who were treated with 250 to 2,000 mug of beclomethasone-dipropionate or equivalent, participated in a parallel-design, double-blind study. Before and after treatment with 0.5 mg/kg/d prednisone or placebo for 14 days, a methacholine challenge was performed. Deep inspiration-induced bronchodilation was measured by the ratio of flow at 40% of FVC on the flow-volume curve after maximal inspiration/flow at 40% of FVC on the flow-volume curve after partial (60% of FVC) inspiration (M/P ratio)., Results: The M/P ratio significantly increased from a mean of 1.31 (range, 1.0 to 1.7) to 1.49 (range, 1.1 to 2.3) in the prednisone group. Interestingly, the improvement in the M/P ratio did not correlate with an accompanying significant increase in PC20 for methacholine (mean change, 1.02; SD doubling dose, 0.97) and a decrease in exhaled nitric oxide (mean change, 14 parts per billion [ppb]; SD, 33.4 ppb)., Conclusions: Systemic antiinflammatory treatment in addition to maintenance therapy with inhaled corticosteroids increases bronchodilation by deep inspiration in patients with mild-to-moderate persistent asthma. This suggests that residual inflammation impairs airway mechanics in asthma patients.