ORCID Profile
0000-0003-3471-5664
Current Organisations
European Respiratory Society
,
Medical University of Graz
,
University of Zurich
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Publications
Consensus statement for inert gas washout measurement using multiple- and single-breath tests
Publisher: European Respiratory Society (ERS)
Date: 08-02-2013
DOI: 10.1183/09031936.00069712
Abstract: Inert gas washout tests, performed using the single- or multiple-breath washout technique, were first described over 60 years ago. As measures of ventilation distribution inhomogeneity, they offer complementary information to standard lung function tests, such as spirometry, as well as improved feasibility across wider age ranges and improved sensitivity in the detection of early lung damage. These benefits have led to a resurgence of interest in these techniques from manufacturers, clinicians and researchers, yet detailed guidelines for washout equipment specifications, test performance and analysis are lacking. This manuscript provides recommendations about these aspects, applicable to both the paediatric and adult testing environment, whilst outlining the important principles that are essential for the reader to understand. These recommendations are evidence based, where possible, but in many places represent expert opinion from a working group with a large collective experience in the techniques discussed. Finally, the important issues that remain unanswered are highlighted. By addressing these important issues and directing future research, the hope is to facilitate the incorporation of these promising tests into routine clinical practice.
Medication Adherence in Patients With Severe Asthma Prescribed Oral Corticosteroids in the U-BIOPRED Cohort
Publisher: Elsevier BV
Date: 07-2021
Normative multiple-breath washout data in school-aged children corrected for sensor error
Publisher: European Respiratory Society (ERS)
Date: 16-06-2022
Structural and Functional Lung Impairment in Primary Ciliary Dyskinesia. Assessment with Magnetic Resonance Imaging and Multiple Breath Washout in Comparison to Spirometry
Publisher: American Thoracic Society
Date: 12-2018
Preschool Multiple-Breath Washout Testing. An Official American Thoracic Society Technical Statement.
Publisher: American Thoracic Society
Date: 03-2018
Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.JACI.2018.05.026
Abstract: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1β, IL-8, and IL-1β. Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
Clinical and transcriptomic features of persistent exacerbation‐prone severe asthma in U‐BIOPRED cohort
Publisher: Wiley
Date: 04-2022
DOI: 10.1002/CTM2.816
Abstract: Exacerbation‐prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U‐BIOPRED cohort. We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short‐acting beta‐agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short‐acting beta‐agonist use and asthma control index. CEA cell adhesion molecule 5 ( CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T‐helper type‐17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.
Consensus statement for inert gas washout measurement using multiple- and single-breath tests. (vol 41, pg 507, 2013)
Publisher: European Respiratory Society (ERS)
Date: 31-10-2013
A Realistic Validation Study of a New Nitrogen Multiple-Breath Washout System
Publisher: Public Library of Science (PLoS)
Date: 27-04-2012
Definitions of non-response and response to biological therapy for severe asthma: a systematic review
Publisher: European Respiratory Society (ERS)
Date: 26-01-2023
DOI: 10.1183/23120541.00444-2022
Abstract: Biologics have proven efficacy for patients with severe asthma but there is lack of consensus on defining response. We systematically reviewed and appraised methodologically developed, defined and evaluated definitions of non-response and response to biologics for severe asthma. We searched four bibliographic databases from inception to 15 March 2021 . Two reviewers screened references, extracted data, and assessed methodological quality of development, measurement properties of outcome measures and definitions of response based on COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). A modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach and narrative synthesis were undertaken. 13 studies reported three composite outcome measures, three asthma symptoms measures, one asthma control measure and one quality of life measure. Only four measures were developed with patient input none were composite measures. Studies utilised 17 definitions of response: 10 out of 17 (58.8%) were based on minimal clinically important difference (MCID) or minimal important difference (MID) and 16 out of 17 (94.1%) had high-quality evidence. Results were limited by poor methodology for the development process and incomplete reporting of psychometric properties. Most measures rated “very low” to “low” for quality of measurement properties and none met all quality standards. This is the first review to synthesise evidence about definitions of response to biologics for severe asthma. While high-quality definitions are available, most are MCIDs or MIDs, which may be insufficient to justify continuation of biologics in terms of cost-effectiveness. There remains an unmet need for universally accepted, patient-centred, composite definitions to aid clinical decision making and comparability of responses to biologics.
Development of Core Outcome Measures sets for paediatric and adult Severe Asthma (COMSA)
Publisher: European Respiratory Society (ERS)
Date: 13-10-2022
DOI: 10.1183/13993003.00606-2022
Abstract: Effectiveness studies with biological therapies for asthma lack standardised outcome measures. The COMSA (Core Outcome Measures sets for paediatric and adult Severe Asthma) Working Group sought to develop Core Outcome Measures (COM) sets to facilitate better synthesis of data and appraisal of biologics in paediatric and adult asthma clinical studies. COMSA utilised a multi-stakeholder consensus process among patients with severe asthma, adult and paediatric clinicians, pharmaceutical representatives, and health regulators from across Europe. Evidence included a systematic review of development, validity and reliability of selected outcome measures plus a narrative review and a pan-European survey to better understand patients’ and carers’ views about outcome measures. It was discussed using a modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) Evidence to Decision framework. Anonymous voting was conducted using predefined consensus criteria. Both adult and paediatric COM sets include forced expiratory volume in 1 s (FEV 1 ) as z-scores, annual frequency of severe exacerbations and maintenance oral corticosteroid use. Additionally, the paediatric COM set includes the Paediatric Asthma Quality of Life Questionnaire and Asthma Control Test or Childhood Asthma Control Test, while the adult COM set includes the Severe Asthma Questionnaire and Asthma Control Questionnaire-6 (symptoms and rescue medication use reported separately). This patient-centred collaboration has produced two COM sets for paediatric and adult severe asthma. It is expected that they will inform the methodology of future clinical trials, enhance comparability of efficacy and effectiveness of biological therapies, and help assess their socioeconomic value. COMSA will inform definitions of non-response and response to biological therapy for severe asthma.
Normative data for multiple breath washout outcomes in school-aged Caucasian children
Publisher: European Respiratory Society (ERS)
Date: 20-12-2019
DOI: 10.1183/13993003.01302-2019
Abstract: The multiple breath nitrogen washout (N 2 MBW) technique is increasingly used to assess the degree of ventilation inhomogeneity in school-aged children with lung disease. However, reference values for healthy children are currently not available. The aim of this study was to generate reference values for N 2 MBW outcomes in a cohort of healthy Caucasian school-aged children. N 2 MBW data from healthy Caucasian school-age children between 6 and 18 years old were collected from four experienced centres. Measurements were performed using an ultrasonic flowmeter (Exhalyzer D, Eco Medics AG, Duernten, Switzerland) and were analysed with commercial software (Spiroware version 3.2.1, Eco Medics AG). Normative values and upper limits of normal (ULN) were generated for lung clearance index (LCI) at 2.5% (LCI 2.5% ) and at 5% (LCI 5% ) of the initial nitrogen concentration and for moment ratios (M 1 /M 0 and M 2 /M 0 ). A prediction equation was generated for functional residual capacity (FRC). Analysis used 485 trials from 180 healthy Caucasian children aged from 6 to 18 years old. While LCI increased with age, this increase was negligible (0.04 units·year –1 for LCI 2.5% ) and therefore fixed ULN were defined for this age group. These limits were 7.91 for LCI 2.5% , 5.73 for LCI 5% , 1.75 for M 1 /M 0 and 6.15 for M 2 /M 0 , respectively. Height and weight were found to be independent predictors of FRC. We report reference values for N 2 MBW outcomes measured on a commercially available ultrasonic flowmeter device (Exhalyzer D, Eco Medics AG) in healthy school-aged children to allow accurate interpretation of ventilation distribution outcomes and FRC in children with lung disease.
Oropharyngeal Microbiota Clusters in Children with Asthma or Wheeze Associate with Allergy, Blood Transcriptomic Immune Pathways, and Exacerbation Risk
Publisher: American Thoracic Society
Date: 15-07-2023
Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U-BIOPRED study
Publisher: European Respiratory Society (ERS)
Date: 25-11-2021
DOI: 10.1183/13993003.01733-2021
Abstract: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort 12–18-month longitudinal s les were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. A total of 90 metabolites were identified, with 40 significantly altered (p .05, false discovery rate .05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10 −20 ), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10 −4 ), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome
Publisher: American Chemical Society (ACS)
Date: 08-05-2018
DOI: 10.1021/ACS.JPROTEOME.8B00018
Abstract: Analysis of induced sputum supernatant is a minimally invasive approach to study the epithelial lining fluid and, thereby, provide insight into normal lung biology and the pathobiology of lung diseases. We present here a novel proteomics approach to sputum analysis developed within the U-BIOPRED (unbiased biomarkers predictive of respiratory disease outcomes) international project. We present practical and analytical techniques to optimize the detection of robust biomarkers in proteomic studies. The normal sputum proteome was derived using data-independent HDMS
The first U-BIOPRED sputum handprint of severe asthma
Publisher: European Respiratory Society
Date: 09-2015
Haemophilus influenzae and Moraxella catarrhalis in sputum of severe asthma with inflammasome and neutrophil activation
Publisher: Wiley
Date: 07-06-2023
DOI: 10.1111/ALL.15776
Abstract: Because of altered airway microbiome in asthma, we analysed the bacterial species in sputum of patients with severe asthma. Whole genome sequencing was performed on induced sputum from non‐smoking (SAn) and current or ex‐smoker (SAs/ex) severe asthma patients, mild/moderate asthma (MMA) and healthy controls (HC). Data were analysed by asthma severity, inflammatory status and transcriptome‐associated clusters (TACs). α‐ ersity at the species level was lower in SAn and SAs/ex, with an increase in Haemophilus influenzae and Moraxella catarrhalis , and Haemophilus influenzae and Tropheryma whipplei , respectively, compared to HC. In neutrophilic asthma, there was greater abundance of Haemophilus influenzae and Moraxella catarrhalis and in eosinophilic asthma, Tropheryma whipplei was increased. There was a reduction in α‐ ersity in TAC1 and TAC2 that expressed high levels of Haemophilus influenzae and Tropheryma whipplei , and Haemophilus influenzae and Moraxella catarrhalis , respectively, compared to HC. Sputum neutrophils correlated positively with Moraxella catarrhalis and negatively with Prevotella , Neisseria and Veillonella species and Haemophilus parainfluenzae . Sputum eosinophils correlated positively with Tropheryma whipplei which correlated with pack‐years of smoking. α‐ and β‐ ersities were stable at one year. Haemophilus influenzae and Moraxella catarrhalis were more abundant in severe neutrophilic asthma and TAC2 linked to inflammasome and neutrophil activation, while Haemophilus influenzae and Tropheryma whipplei were highest in SAs/ex and in TAC1 associated with highest expression of IL‐13 type 2 and ILC2 signatures with the abundance of Tropheryma whipplei correlating positively with sputum eosinophils. Whether these bacterial species drive the inflammatory response in asthma needs evaluation.
Asthma and Wheeze Severity and the Oropharyngeal Microbiota in Children and Adolescents
Publisher: American Thoracic Society
Date: 12-2022
Alternate gas washout indices: Assessment of ventilation inhomogeneity in mild to moderate pediatric cystic fibrosis lung disease
Publisher: Wiley
Date: 30-08-2018
DOI: 10.1002/PPUL.24149
Abstract: Normalized phase III slope (Sn We measured nitrogen MBW and spirometry in 135 children (43 controls) aged 4-18 years. We assessed validity, practicability, and reliability of Sn Lung clearance index (LCI) was abnormal in 80 (87%), Scond in 55 (60%), Scond* in 17 (19%), Sacin in 10 (11%), Sacin* in 11 (12%), and FEV In children with mild-to-moderate CF lung disease, alternate protocols seem practical but clinimetric properties of standard Sn
Urinary Leukotriene E4and Prostaglandin D2Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation. A Clinical Observational Study
Publisher: American Thoracic Society
Date: 2021
Association of lung clearance index with survival in individuals with cystic fibrosis.
Publisher: European Respiratory Society (ERS)
Date: 21-07-2022
DOI: 10.1183/13993003.00432-2021
Abstract: The lung clearance index (LCI) assesses global ventilation inhomogeneity and is a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease. We examined the association of LCI with the risk of death or lung transplantation (LTx) in in iduals with CF. We performed a retrospective analysis in a cohort of in iduals with CF aged ≥5 years with LCI and forced expired volume in 1 s (FEV In total, 237 in iduals with CF with a mean (range) age of 13.9 (5.6-41.0) years were included. The time-to-event analysis accrued 3813 person-years and 94 (40%) in iduals died or received LTx. Crude hazard ratios were 1.04 (95% CI 1.01-1.06) per 1.0 z-score increase in LCI and 1.25 (95% CI 1.11-1.41) per 1.0 z-score decrease in FEV Increased ventilation inhomogeneity is associated with greater risk of death or LTx. Our data support LCI as novel surrogate of survival in in iduals with CF.
The first U-BIOPRED blood handprint of severe asthma
Publisher: European Respiratory Society
Date: 09-2015
Late Breaking Abstract - Longitudinal analysis of variation in clinical features from the U-BIOPRED severe asthma cohort
Publisher: European Respiratory Society
Date: 15-09-2018
eNose breath prints as a surrogate biomarker for classifying patients with asthma by atopy
Publisher: Elsevier BV
Date: 11-2020
Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort
Publisher: Public Library of Science (PLoS)
Date: 21-09-2018
Nasal Resistome Development in Infants With Cystic Fibrosis in the First Year of Life
Publisher: Frontiers Media SA
Date: 26-02-2019
Discordant use of short‐acting β2 agonists in children and adults with severe, uncontrolled asthma from the U‐BIOPRED cohort
Publisher: Wiley
Date: 24-11-2020
DOI: 10.1002/PPUL.25171
Effect of intermittent inspiratory leaks on measurement of lung clearance index using nitrogen and sulfur hexafluoride
Publisher: European Respiratory Society (ERS)
Date: 10-2018
U-BIOPRED accessible handprint: combining omics platforms to identify stable asthma subphenotypes
Publisher: European Respiratory Society
Date: 15-09-2018
IL-17–high asthma with features of a psoriasis immunophenotype
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JACI.2019.03.027
Abstract: The role of IL-17 immunity is well established in patients with inflammatory diseases, such as psoriasis and inflammatory bowel disease, but not in asthmatic patients, in whom further study is required. We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity. Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood s les (n = 498) from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. Gene signatures induced in vitro by IL-17 and IL-13 in bronchial epithelial cells were used to identify patients with IL-17-high and IL-13-high asthma phenotypes. Twenty-two of 91 patients were identified with IL-17, and 9 patients were identified with IL-13 gene signatures. The patients with IL-17-high asthma were characterized by risk of frequent exacerbations, airway (sputum and mucosal) neutrophilia, decreased lung microbiota ersity, and urinary biomarker evidence of activation of the thromboxane B2 pathway. In pathway analysis the differentially expressed genes in patients with IL-17-high asthma were shared with those reported as altered in psoriasis lesions and included genes regulating epithelial barrier function and defense mechanisms, such as IL1B, IL6, IL8, and β-defensin. The IL-17-high asthma phenotype, characterized by bronchial epithelial dysfunction and upregulated antimicrobial and inflammatory response, resembles the immunophenotype of psoriasis, including activation of the thromboxane B2 pathway, which should be considered a biomarker for this phenotype in further studies, including clinical trials targeting IL-17.
Longitudinal monitoring of pediatric cystic fibrosis lung disease using nitrite in exhaled breath condensate
Publisher: Wiley
Date: 29-10-2007
DOI: 10.1002/PPUL.20719
Abstract: Cystic fibrosis (CF) lung disease is characterized by airway inflammation and airway infection. Nitrites in exhaled breath condensate (EBC-NO(2)(-)) have been shown to be increased in children and adults with CF compared to healthy controls suggesting its use as a measure of airway inflammation. This longitudinal study aimed to evaluate if repeated measurements of EBC-NO(2)(-) are helpful in monitoring CF lung disease activity in children. Thirty-two children with mild CF lung disease (age 10.6 +/- 3.3 years) were recruited in two study centers. Follow-up visits occurred every 3 months over a period of 1 year with a total of five visits. Each visit included a clinical assessment incorporating a modified Shwachman-Kulczycki (SK) score, spirometry, an oropharyngeal swab, or sputum s le for bacterial analysis and an EBC s le analyzed for NO(2)(-) using a spectrophotometric assay. Furthermore at the first and the last visit a chest radiograph was done and scored (Chrispin-Norman (CN) score). There was no correlation of EBC-NO(2)(-) and parameters of spirometry, SK-score, or CN-score. Furthermore, increased EBC-NO(2)(-) levels did not predict subsequent pulmonary exacerbations. We conclude that repeated measurements of EBC-NO(2)(-) are not helpful in the longitudinal monitoring of mild CF lung disease in children.
Late Breaking Abstract - Comparison of the blood transcriptomic profiles of adults and children from the U-BIOPRED asthma study
Publisher: European Respiratory Society
Date: 09-2017
Leaks during multiple-breath washout: characterisation and influence on outcomes
Publisher: European Respiratory Society (ERS)
Date: 2018
DOI: 10.1183/23120541.00012-2017
Abstract: Nitrogen multiple-breath washout (N 2 MBW) is increasingly used in patients with cystic fibrosis. The current European Respiratory Society/American Thoracic Society consensus statement for MBW recommends the rejection of measurements with leaks. However, it is unclear whether this is necessary for all types of leaks. Here, our aim was to 1) model and 2) apply air leaks, and 3) to assess their influence on the primary MBW outcomes of lung clearance index and functional residual capacity. We investigated the influence of air leaks at various locations (pre-, intra- and post-capillary), sizes, durations and stages of the washout. Modelled leaks were applied to existing N 2 MBW data from 10 children by modifying breath tables. In addition, leaks were applied to the equipment during N 2 MBW measurements performed by one healthy adolescent. All modelled and applied leaks resulted in statistically significant but heterogeneous effects on lung clearance index and functional residual capacity. In all types of continuous inspiratory leaks exceeding a certain size, the end of the washout was not reached. For practical application, we illustrated six different “red flags”, i.e. signs that enable easy identification of leaks during measurements. Air leaks during measurement significantly influence N 2 MBW outcomes. The influence of leaks on MBW outcomes is dependent on the location, relation to breath cycle, duration, stage of washout and size of the leak. We identified a range of signs to help distinguish leaks from physiological noise.
Topological data analysis (TDA) of U-BIOPRED paediatric peripheral blood gene expression identified asthma phenotypes characterised by alternative splicing of glucocorticoid receptor (GR) mRNA
Publisher: European Respiratory Society
Date: 15-09-2018
Ventilation and perfusion assessed by functional MRI in children with CF: reproducibility in comparison to lung function
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.JCF.2018.10.003
Abstract: Chronic lung diseases such as cystic fibrosis (CF) can be monitored by imaging and lung function modalities. Magnetic resonance imaging (MRI) techniques such as matrix pencil (MP) decomposition allows for evaluation of regional impairment of fractional ventilation (R Twenty-threeCF and 12 healthy school-aged children underwent MRI and lung function tests on the same day on two occasions 24 h apart. Global ventilation inhomogeneity was assessed by the lung clearance index (LCI) from nitrogen-multiple breath washout (N Sixty-nine measurements from MP MRI and N Functional imaging is reproducible and short-term changes in R
U-BIOPRED clinical adult asthma clusters linked to a subset of sputum omics
Publisher: Elsevier BV
Date: 06-2017
DOI: 10.1016/J.JACI.2016.08.048
Abstract: Asthma is a heterogeneous disease in which there is a differential response to asthma treatments. This heterogeneity needs to be evaluated so that a personalized management approach can be provided. We stratified patients with moderate-to-severe asthma based on clinicophysiologic parameters and performed an omics analysis of sputum. Partition-around-medoids clustering was applied to a training set of 266 asthmatic participants from the European Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes (U-BIOPRED) adult cohort using 8 prespecified clinic-physiologic variables. This was repeated in a separate validation set of 152 asthmatic patients. The clusters were compared based on sputum proteomics and transcriptomics data. Four reproducible and stable clusters of asthmatic patients were identified. The training set cluster T1 consists of patients with well-controlled moderate-to-severe asthma, whereas cluster T2 is a group of patients with late-onset severe asthma with a history of smoking and chronic airflow obstruction. Cluster T3 is similar to cluster T2 in terms of chronic airflow obstruction but is composed of nonsmokers. Cluster T4 is predominantly composed of obese female patients with uncontrolled severe asthma with increased exacerbations but with normal lung function. The validation set exhibited similar clusters, demonstrating reproducibility of the classification. There were significant differences in sputum proteomics and transcriptomics between the clusters. The severe asthma clusters (T2, T3, and T4) had higher sputum eosinophilia than cluster T1, with no differences in sputum neutrophil counts and exhaled nitric oxide and serum IgE levels. Clustering based on clinicophysiologic parameters yielded 4 stable and reproducible clusters that associate with different pathobiological pathways.
Association of lung clearance index with survival in individuals with cystic fibrosis
Publisher: Cold Spring Harbor Laboratory
Date: 25-06-2021
DOI: 10.1101/2021.06.25.21254759
Abstract: Lung clearance index (LCI) quantifies global ventilation inhomogeneity, a sensitive biomarker of airway function in cystic fibrosis (CF) lung disease. We examined the association of LCI with the risk of death or lung transplantation (LTX) in in iduals with CF. We performed a retrospective analysis in a cohort of in iduals with CF aged ≥ five years with available LCI and FEV 1 measurements between 1980 and 2006. Outcome was time until death or LTX. We applied Cox proportional hazard regressions using the earliest available LCI and FEV 1 values and adjusted for demographic and clinical variables. For sensitivity analyses, we used the mean of the first three LCI and FEV 1 measurements, stratified the cohort based on age, and investigated in iduals with normal FEV 1 . In total, 237 in iduals with CF aged mean (range) 13.9 (5.6–41.0) years were included. This time-to-event analysis accrued 3813 person-years, 94 (40%) in iduals died or received LTX. Crude hazard ratios [95% CI] were 1.04 [1.01–1.06] per one z-score increase in LCI and 1.25 [1.11–1.41] per one z-score decrease in FEV 1 . After adjusting LCI and FEV 1 mutually in addition to sex, age, BMI and the number of hospitalisations, hazard ratios were 1.04 [1.01-1.07] for LCI, and 1.12 [0.95-1.33] for FEV 1 . Sensitivity analyses yielded similar results and using the mean LCI strengthened the associations. Increased ventilation inhomogeneity is associated with greater risk of death or LTX. Our data support LCI as novel surrogate of survival in in iduals with CF. Lung clearance index (LCI) is a measure of global ventilation inhomogeneity which increases early during the course of Cystic Fibrosis (CF) lung disease. This study shows that LCI is predictive of death or lung transplantation in in iduals with CF. NCT04016194
Pathway discovery using transcriptomic profiles in adult-onset severe asthma
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.JACI.2017.06.037
Abstract: Adult-onset severe asthma is characterized by highly symptomatic disease despite high-intensity asthma treatments. Understanding of the underlying pathways of this heterogeneous disease is needed for the development of targeted treatments. Gene set variation analysis is a statistical technique used to identify gene profiles in heterogeneous s les. We sought to identify gene profiles associated with adult-onset severe asthma. This was a cross-sectional, observational study in which adult patients with adult-onset of asthma (defined as starting at age ≥18 years) as compared with childhood-onset severe asthma (<18 years) were selected from the U-BIOPRED cohort. Gene expression was assessed on the total RNA of induced sputum (n = 83), nasal brushings (n = 41), and endobronchial brushings (n = 65) and biopsies (n = 47) (Affymetrix HT HG-U133+ PM). Gene set variation analysis was used to identify differentially enriched predefined gene signatures of leukocyte lineage, inflammatory and induced lung injury pathways. Significant differentially enriched gene signatures in patients with adult-onset as compared with childhood-onset severe asthma were identified in nasal brushings (5 signatures), sputum (3 signatures), and endobronchial brushings (6 signatures). Signatures associated with eosinophilic airway inflammation, mast cells, and group 3 innate lymphoid cells were more enriched in adult-onset severe asthma, whereas signatures associated with induced lung injury were less enriched in adult-onset severe asthma. Adult-onset severe asthma is characterized by inflammatory pathways involving eosinophils, mast cells, and group 3 innate lymphoid cells. These pathways could represent useful targets for the treatment of adult-onset severe asthma.
Measures of adherence in patients with severe asthma prescribed systemic steroids in the U-BIOPRED cohort
Publisher: European Respiratory Society
Date: 15-09-2018
Stratification of asthma by lipidomic profiling of induced sputum supernatant
Publisher: Elsevier BV
Date: 07-2023
Treatable traits in the European U‐BIOPRED adult asthma cohorts
Publisher: Wiley
Date: 12-11-2018
DOI: 10.1111/ALL.13629
Lung clearance index (LCI) based on four different alveolar N2estimates in a large reference population aged 6-86 years
Publisher: European Respiratory Society
Date: 09-2015
Related Organisations
European Respiratory Society
Location: United Kingdom of Great Britain and Northern Ireland
Inselspital Universitätsspital Bern Kinderklinik
Location: Switzerland
Related Funding Activities
No related grants have been discovered for Florian Singer.