| 1. |
- Brinkman, Paul, et al.
(författare)
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Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:5, s. 1811-1820.e7
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe asthma is a heterogeneous condition, as shown by independent cluster analyses based on demographic, clinical, and inflammatory characteristics. A next step is to identify molecularly driven phenotypes using “omics” technologies. Molecular fingerprints of exhaled breath are associated with inflammation and can qualify as noninvasive assessment of severe asthma phenotypes.Objectives: We aimed (1) to identify severe asthma phenotypes using exhaled metabolomic fingerprints obtained from a composite of electronic noses (eNoses) and (2) to assess the stability of eNose-derived phenotypes in relation to withinpatient clinical and inflammatory changes.Methods: In this longitudinal multicenter study exhaled breath samples were taken from an unselected subset of adults with severe asthma from the U-BIOPRED cohort. Exhaled metabolites were analyzed centrally by using an assembly of eNoses. Unsupervised Ward clustering enhanced by similarity profile analysis together with K-means clustering was performed. For internal validation, partitioning around medoids and topological data analysis were applied. Samples at 12 to 18 months of prospective follow-up were used to assess longitudinal within-patient stability.Results: Data were available for 78 subjects (age, 55 years [interquartile range, 45-64 years]; 41% male). Three eNosedriven clusters (n = 26/33/19) were revealed, showing differences in circulating eosinophil (P = .045) and neutrophil (P = .017) percentages and ratios of patients using oral corticosteroids (P = .035). Longitudinal within-patient cluster stability was associated with changes in sputum eosinophil percentages (P = .045).Conclusions: We have identified and followed up exhaled molecular phenotypes of severe asthma, which were associated with changing inflammatory profile and oral steroid use. This suggests that breath analysis can contribute to the management of severe asthma.
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| 2. |
- Östling, Jörgen, et al.
(författare)
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IL-17-high asthma with features of a psoriasis immunophenotype
- 2019
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 144:5, s. 1198-1213
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Tidskriftsartikel (refereegranskat)abstract
- Background: 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.Objective: We sought to undertake a deep phenotyping study of asthmatic patients with upregulated IL-17 immunity.Methods: Whole-genome transcriptomic analysis was performed by using epithelial brushings, bronchial biopsy specimens (91 asthmatic patients and 46 healthy control subjects), and whole blood samples (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.Results: 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 diversity, 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.Conclusion: 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.
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| 3. |
- Alahmadi, Fahad, et al.
(författare)
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Measures of adherence in patients with severe asthma prescribed systemic steroids in the U-BIOPRED cohort
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Rates of sub-optimal adherence to medications in asthma range up to 70%; the impact in severe asthma is likely to be particularly high. We measured self-reported adherence in participants in the U-BIOPRED cohort prescribed daily prednisolone using the Medication Adherence Response Scale (MARS), and compared to measured urinary prednisolone and metabolites in order to determine: 1. the prevalence of suboptimal adherence by each method; 2. the ability of MARS to predict urinary steroid detection.Methods: Participants completed the MARS, and/or provided urine samples (analysed for prednisolone and metabolites by LCMS). The performance characteristics of the MARS predicting undetected urinary steroid were calculated in the subgroup having both tests.Results: 181 participants currently taking regular oral corticosteroids were included, 59% female, mean (SD) age 54(12)yrs, FEV1 64.7(20.4)% predicted. Sub-optimal adherence (MARS score < 4.5) was reported in 62 participants, and 76 did not have detectable urinary prednisolone or metabolites. Good adherence by both methods was detected in only 52 participants (34%, see table). There was no difference in daily prednisolone dose between detectable and undetectable metabolites groups (p=0.848).Conclusion: Low levels of adherence to treatment in severe asthma is a common problem, when measured either directly or self-reported. There was very poor agreement (48% concordance) between these two methods, and we suggest that, for now both approaches should be used.
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| 4. |
- Backman, Helena, et al.
(författare)
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Eosinophilic inflammation and lung function decline in a long-term follow-up of a large population-based asthma cohort
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The relationship between lung function decline and airway inflammation among asthmatics has important therapeutic implications, but has rarely been studied in large samples or in population-based asthma cohorts.A population-based adult asthma cohort (n=2055) was recruited during 1986-2001 and clinically examined including spirometry. In 2012-2014, all still eligible subjects (n=1425) were invited to a clinical follow-up including spirometry, blood sampling, and a structured interview, and n=1006 participated (55% women, mean age 59y, 32-92y). Linear regression was performed with age, sex, smoking habits, year of first examination, family history of asthma, socioeconomic status, eosinophils (EOS)>=0.3x109/L, and neutrophils (NEUT)>=5.0x109/L as independent variables and pre-bronchodilator FEV1 decline/year (ml and % of predicted [pp], respectively) as dependent. In secondary models, both ICS use at baseline and ICS use at follow-up were also included.The mean annual FEV1 decline in ml (pp) among asthmatics with EOS<0.3, 0.4>EOS>=0.3 and EOS>=0.4x109/L, respectively, was 26ml (0.03pp), 29ml (0.10pp) and 34ml (0.27pp) (p<0.001). In adjusted analyses, EOS>=0.3 was significantly associated with FEV1 decline, both in terms of ml (4ml excess annual decline vs EOS<0.3) and pp. The association between EOS and FEV1 decline in pp, but not ml, remained when additionally adjusted for ICS use. The association with NEUT>=5.0x109/L was less clear.On group level, adult asthmatics with higher levels of eosinophils in blood have a history of excess FEV1 decline compared to asthmatics with lower levels of eosinophil inflammation, independent of other factors such as ICS use.
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| 5. |
- Backman, Helena, et al.
(författare)
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Severe asthma : A population study perspective
- 2019
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Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 49:6, s. 819-828
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSevere asthma is a considerable challenge for patients, health care professionals and society. Few studies have estimated the prevalence of severe asthma according to modern definitions of which none based on a population study.ObjectiveTo describe characteristics and estimate the prevalence of severe asthma in a large adult population‐based asthma cohort followed for 10‐28 years.MethodsN=1006 subjects with asthma participated in a follow‐up during 2012‐14, when 830 (mean age 59y, 56% women) still had current asthma. Severe asthma was defined according to three internationally well‐known criteria: the ATS workshop definition from 2000 used in the US Severe Asthma Research Program (SARP), the 2014 ATS/ERS Task force definition and the GINA 2017. All subjects with severe asthma according to any of these criteria were undergoing respiratory specialist care, and were also contacted by telephone to verify treatment adherence.ResultsThe prevalence of severe asthma according to the three definitions was 3.6% (US SARP), 4.8% (ERS/ATS Taskforce), and 6.1% (GINA) among subjects with current asthma. Although all were using high ICS doses and other maintenance treatment, >40% had uncontrolled asthma according to the asthma control test. Severe asthma was related to age >50 years, nasal polyposis, impaired lung function, sensitization to aspergillus, and tended to be more common in women. Further, neutrophils in blood significantly discriminated severe asthma from other asthma.Conclusions and clinical relevanceSevere asthma differed significantly from other asthma in terms of demographic, clinical and inflammatory characteristics, results suggesting possibilities for improved treatment regimens of severe asthma. The prevalence of severe asthma in this asthma cohort was 4‐6%, corresponding to approximately 0.5% of the general population.
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| 6. |
- Backman, Helena, et al.
(författare)
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Severe asthma among adults : Prevalence and clinical characteristics
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Severe asthma is a considerable challenge for patients, health care professionals and society. Few studies have estimated the prevalence of severe asthma according to modern definitions of which none based on a population study.Methods: We estimated the prevalence and studied characteristics of severe asthma in a large adult population-based asthma cohort followed for 10-28 years in northern Sweden: 1006 subjects participated in a follow-up during 2012-14, when 830 (82.5%) still had current asthma (mean age 59y, 32-92y, 56% women). Severe asthma was defined according to three internationally well-known criteria: the US SARP, ATS/ERS and GINA. All subjects with severe asthma were undergoing respiratory specialist care, and were also contacted by telephone to verify adherence to treatment.Results: The prevalence of severe asthma according to the three definitions was 3.6% (US SARP), 4.8% (ERS/ATS), and 6.1% (GINA) among subjects with current asthma. Although all were using high ICS doses and other maintenance treatment, >40% had uncontrolled asthma and <10% had controlled asthma according to the ACT. Severe asthma was related to age >50 years, nasal polyposis, decreased FEV1, not fully reversible airway obstruction, sensitization to aspergillus, elevated neutrophils and partly to eosinophils, and tended to be more common in women.Conclusion: The prevalence of severe asthma in this asthma cohort was 4-6%, corresponding to approximately 0.5% of the population in northern Sweden. A substantial proportion of those with severe asthma had uncontrolled disease, and severe asthma differed significantly from other asthma in terms of both clinical and inflammatory characteristics.
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| 7. |
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| 8. |
- Brandsma, Joost, et al.
(författare)
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Lipid phenotyping of lung epithelial lining fluid in healthy human volunteers
- 2018
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Ingår i: Metabolomics. - : Springer-Verlag New York. - 1573-3882 .- 1573-3890. ; 14:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lung epithelial lining fluid (ELF)-sampled through sputum induction-is a medium rich in cells, proteins and lipids. However, despite its key role in maintaining lung function, homeostasis and defences, the composition and biology of ELF, especially in respect of lipids, remain incompletely understood. Objectives: To characterise the induced sputum lipidome of healthy adult individuals, and to examine associations between different ELF lipid phenotypes and the demographic characteristics within the study cohort.Methods: Induced sputum samples were obtained from 41 healthy non-smoking adults, and their lipid compositions analysed using a combination of untargeted shotgun and liquid chromatography mass spectrometry methods. Topological data analysis (TDA) was used to group subjects with comparable sputum lipidomes in order to identify distinct ELF phenotypes.Results: The induced sputum lipidome was diverse, comprising a range of different molecular classes, including at least 75 glycerophospholipids, 13 sphingolipids, 5 sterol lipids and 12 neutral glycerolipids. TDA identified two distinct phenotypes differentiated by a higher total lipid content and specific enrichments of diacyl-glycerophosphocholines, -inositols and -glycerols in one group, with enrichments of sterols, glycolipids and sphingolipids in the other. Subjects presenting the lipid-rich ELF phenotype also had significantly higher BMI, but did not differ in respect of other demographic characteristics such as age or gender.Conclusions: We provide the first evidence that the ELF lipidome varies significantly between healthy individuals and propose that such differences are related to weight status, highlighting the potential impact of (over)nutrition on lung lipid metabolism.
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| 9. |
- Burg, Dominic, et al.
(författare)
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Large-Scale Label-Free Quantitative Mapping of the Sputum Proteome
- 2018
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 17:6, s. 2072-2091
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Tidskriftsartikel (refereegranskat)abstract
- Analysis of induced sputum supematant 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 HDMSE applied to 40 healthy nonsmoking participants, which provides an essential baseline from which to compare modulation of protein expression in respiratory diseases. The "core" sputum proteome (proteins detected in >= 40% of participants) was composed of 284 proteins, and the extended proteome (proteins detected in >= 3 participants) contained 1666 proteins. Quality control procedures were developed to optimize the accuracy and consistency of measurement of sputum proteins and analyze the distribution of sputum proteins in the healthy population. The analysis showed that quantitation of proteins by HDMSE is influenced by several factors, with some proteins being measured in all participants' samples and with low measurement variance between samples from the same patient. The measurement of some proteins is highly variable between repeat analyses, susceptible to sample processing effects, or difficult to accurately quantify by mass spectrometry. Other proteins show high interindividual variance. We also highlight that the sputum proteome of healthy individuals is related to sputum neutrophil levels, but not gender or allergic sensitization. We illustrate the importance of design and interpretation of disease biomarker studies considering such protein population and technical measurement variance.
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| 10. |
- Emma, Rosalia, et al.
(författare)
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Enhanced oxidative stress in smoking and ex-smoking severe asthma in the U-BIOPRED cohort
- 2018
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative stress is believed to be a major driver of inflammation in smoking asthmatics. The U-BIOPRED project recruited a cohort of Severe Asthma smokers/ex-smokers (SAs/ex) and non-smokers (SAn) with extensive clinical and biomarker information enabling characterization of these subjects. We investigated oxidative stress in severe asthma subjects by analysing urinary 8-iso-PGF(2 alpha) and the mRNA-expression of the main pro-oxidant (NOX2; NOSs) and anti-oxidant (SODs; CAT; GPX1) enzymes in the airways of SAs/ex and SAn. All the severe asthma U-BIOPRED subjects were further divided into current smokers with severe asthma (CSA), ex-smokers with severe asthma (ESA) and non-smokers with severe asthma (NSA) to deepen the effect of active smoking. Clinical data, urine and sputum were obtained from severe asthma subjects. A bronchoscopy to obtain bronchial biopsy and brushing was performed in a subset of subjects. The main clinical data were analysed for each subset of subjects (urine-8-iso-PGF(2 alpha); IS-transcriptomics; BB-transcriptomics; BBrtranscriptomics). Urinary 8-iso-PGF(2 alpha) was quantified using mass spectrometry. Sputum, bronchial biopsy and bronchial brushing were processed for mRNA expression microarray analysis. Urinary 8-iso-PGF(2 alpha) was increased in SAs/ex, median (IQR) = 31.7 (24.5 +/- 44.7) ng/mmol creatinine, compared to SAn, median (IQR) = 26.6 (19.6 +/- 36.6) ng/mmol creatinine (p< 0.001), and in CSA, median (IQR) = 34.25 (24.4 +/- 47.7), vs. ESA, median (IQR) = 29.4 (22.3 +/- 40.5), and NSA, median (IQR) = 26.5 (19.6 +/- 16.6) ng/mmol creatinine (p = 0.004). Sputum mRNA expression of NOX2 was increased in SAs/ex compared to SAn (probe sets 203922_PM_s_at fold-change = 1.05 p = 0.006; 203923_PM_s_at fold-change = 1.06, p = 0.003; 233538_PM_s_at fold-change = 1.06, p = 0.014). The mRNA expression of antioxidant enzymes were similar between the two severe asthma cohorts in all airway samples. NOS2 mRNA expression was decreased in bronchial brushing of SAs/ex compared to SAn (fold-change = -1.10; p = 0.029). NOS2 mRNA expression in bronchial brushing correlated with FeNO (Kendal's Tau = 0.535; p< 0.001). From clinical and inflammatory analysis, FeNO was lower in CSA than in ESA in all the analysed subject subsets (p< 0.01) indicating an effect of active smoking. Results about FeNO suggest its clinical limitation, as inflammation biomarker, in severe asthma active smokers. These data provide evidence of greater systemic oxidative stress in severe asthma smokers as reflected by a significant changes of NOX2 mRNA expression in the airways, together with elevated urinary 8-iso-PGF(2 alpha) in the smokers/ex-smokers group.
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