| 1. |
- Andreasson, Louise Munkholm, et al.
(författare)
-
Airway hyperresponsiveness correlates with airway TSLP in asthma independent of eosinophilic inflammation
-
Ingår i: Journal of Allergy and Clinical Immunology. - 0091-6749.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Thymic stromal lymphopoietin (TSLP) is released from the airway epithelium in response to various environmental triggers, inducing a type-2 inflammatory response, and is associated with airway inflammation, airway hyperresponsiveness (AHR), and exacerbations. TSLP may also induce AHR via a direct effect on airway smooth muscle and mast cells, independently of type-2 inflammation, although association between airway TSLP and AHR across asthma phenotypes has been described sparsely. Objectives: This study sought to investigate the association between AHR and levels of TSLP in serum, sputum, and bronchoalveolar lavage in patients with asthma with and without type-2 inflammation. Methods: A novel ultrasensitive assay was used to measure levels of TSLP in patients with asthma (serum, n = 182; sputum, n = 81; bronchoalveolar lavage, n = 85) and healthy controls (serum, n = 47). The distribution and association among airway and systemic TSLP, measures of AHR, type-2 inflammation, and severity of disease were assessed. Results: TSLP in sputum was associated with AHR independently of levels of eosinophils and fractional exhaled nitric oxide (ρ = 0.49, P = .005). Serum TSLP was higher in both eosinophil-high and eosinophil-low asthma compared to healthy controls: geometric mean: 1600 fg/mL (95% CI: 1468-1744 fg/mL) and 1294 fg/mL (95% CI: 1167-1435 fg/mL) versus 846 fg/mL (95% CI: 661-1082 fg/mL), but did not correlate with the level of AHR. Increasing age, male sex, and eosinophils in blood were associated with higher levels of TSLP in serum, whereas lung function, inhaled corticosteroid dose, and symptom score were not. Conclusions: The association between TSLP in sputum and AHR to mannitol irrespective of markers of type-2 inflammation further supports a role of TSLP in AHR that is partially independent of eosinophilic inflammation.
|
|
| 2. |
- Backer, Vibeke, et al.
(författare)
-
Clinical characteristics of the BREATHE cohort–a real-life study on patients with asthma and COPD
- 2020
-
Ingår i: European clinical respiratory journal. - : Informa UK Limited. - 2001-8525. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The BREATHE study is a cross-sectional study of real-life patients with asthma and/or COPD in Denmark and Sweden aiming to increase the knowledge across severities and combinations of obstructive airway disease. Design: Patients with suspicion of asthma and/or COPD and healthy controls were invited to participate in the study and had a standard evaluation performed consisting of questionnaires, physical examination, FeNO and lung function, mannitol provocation test, allergy test, and collection of sputum and blood samples. A subgroup of patients and healthy controls had a bronchoscopy performed with a collection of airway samples. Results: The study population consisted of 1403 patients with obstructive airway disease (859 with asthma, 271 with COPD, 126 with concurrent asthma and COPD, 147 with other), and 89 healthy controls (smokers and non-smokers). Of patients with asthma, 54% had moderate-to-severe disease and 46% had mild disease. In patients with COPD, 82% had groups A and B, whereas 18% had groups C and D classified disease. Patients with asthma more frequently had childhood asthma, atopic dermatitis, and allergic rhinitis, compared to patients with COPD, asthma + COPD and Other, whereas FeNO levels were higher in patients with asthma and asthma + COPD compared to COPD and Other (18 ppb and 16 ppb vs 12.5 ppb and 14 ppb, p < 0.001). Patients with asthma, asthma + COPD and Other had higher sputum eosinophilia (1.5%, 1.5%, 1.2% vs 0.75%, respectively, p < 0.001) but lower sputum neutrophilia (39.3, 43.5%, 40.8% vs 66.8%, p < 0.001) compared to patients with COPD. Conclusions: The BREATHE study provides a unique database and biobank with clinical information and samples from 1403 real-life patients with asthma, COPD, and overlap representing different severities of the diseases. This research platform is highly relevant for disease phenotype- and biomarker studies aiming to describe a broad spectrum of obstructive airway diseases.
|
|
| 3. |
- Berlin, Frida, et al.
(författare)
-
Mast Cell Tryptase Promotes Airway Remodeling by Inducing Anti-Apoptotic and Cell Growth Properties in Human Alveolar and Bronchial Epithelial Cells
- 2023
-
Ingår i: Cells. - 2073-4409. ; 12:10
-
Tidskriftsartikel (refereegranskat)abstract
- Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the implication of intraepithelial MCs on the local environment, such as epithelial cell function and properties. In this study, we investigated whether MC tryptase is involved in bronchial and alveolar remodeling and the mechanisms of regulation during inflammation. Using novel holographic live cell imaging, we found that MC tryptase enhanced human bronchial and alveolar epithelial cell growth and shortened the cell division intervals. The elevated cell growth induced by tryptase remained in a pro-inflammatory state. Tryptase also increased the expression of the anti-apoptotic protein BIRC3, as well as growth factor release in epithelial cells. Thus, our data imply that the intraepithelial and alveolar MC release of tryptase may play a critical role in disturbing bronchial epithelial and alveolar homeostasis by altering cell growth–death regulation.
|
|
| 4. |
- Cerps, Samuel, et al.
(författare)
-
House dust mite sensitization and exposure affects bronchial epithelial anti-microbial response to viral stimuli in patients with asthma
- 2022
-
Ingår i: Allergy: European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538. ; 77:8, s. 2498-2508
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Allergen exposure worsens viral-triggered asthma exacerbations and could predispose the host to secondary bacterial infections. We have previously demonstrated that exposure to house dust mite (HDM) reduced TLR-3-induced IFN-β in human bronchial epithelial cells (HBECs) from healthy donors. We hypothesize that HDM sensitization in different ways may be involved in both viral and bacterial resistance of HBECs in asthma. In this study, the role of HDM sensitization and effects of HDM exposure on viral stimulus-challenged HBECs from asthmatic donors have been explored with regard to expression and release of molecules involved in anti-viral and anti-bacterial responses, respectively. Methods: HBECs from HDM-sensitized (HDM+) and unsensitized (HDM-) patients with asthma were used. HBECs were exposed to HDM or heat inactivated (hi)-HDM (20 μg/ml) for 24 h prior to stimulation with the viral infection mimic, Poly(I:C), for 3 or 24 h. Samples were analyzed with ELISA and RT-qPCR for β-defensin-2, IFN-β, TSLP, and neutrophil-recruiting mediators: IL-8 and TNF-⍺. NFκB signaling proteins p105, p65, and IκB-⍺ were analyzed by Western blot. Results: Poly(I:C)-induced IFN-β expression was reduced in HBECs from HDM + compared to HDM- patients (p = 0.05). In vitro exposure of HBECs to HDM furthermore reduced anti-microbial responses to Poly(I:C) including β-defensin-2, IL-8, and TNF-⍺, along with reduced NFκB activity. This was observed in HBECs from asthma patients sensitized to HDM, as well as in non-sensitized patients. By contrast, Poly (I:C)-induced release of TSLP, a driver of T2 inflammation, was not reduced with exposure to HDM. Conclusion: Using HBECs challenged with viral infection mimic, Poly(I:C), we demonstrated that allergic sensitization to HDM was associated with impaired anti-viral immunity and that HDM exposure reduced anti-viral and anti-bacterial defense molecules, but not TSLP, across non-allergic as well as allergic asthma. These data suggest a role of HDM in the pathogenesis of asthma exacerbations evoked by viral infections including sequential viral-bacterial and viral-viral infections.
|
|
| 5. |
- Frøssing, Laurits, et al.
(författare)
-
Distribution of type 2 biomarkers and association with severity, clinical characteristics and comorbidities in the BREATHE real-life asthma population
- 2023
-
Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 9:2
-
Tidskriftsartikel (refereegranskat)abstract
- Background Type 2 (T2) high asthma is recognised as a heterogenous entity consisting of several endotypes; however, the prevalence and distribution of the T2 biomarkers in the general asthma population, across asthma severity, and across compartments is largely unknown. The objective of the present study was to describe expression and overlaps of airway and systemic T2 biomarkers in a clinically representative asthma population. Methods Patients with asthma from the real-life BREATHE cohort referred to a specialist centre were included and grouped according to T2 biomarkers: blood and sputum eosinophilia (⩾0.3×109 cells·L−1 and 3% respectively), total IgE (⩾150 U·mL−1), and fractional exhaled nitric oxide (⩾25 ppb). Results Patients with mild-to-moderate asthma were younger (41 versus 49 years, p<0.001), had lower body mass index (25.9 versus 28.0 kg·m−2, p=0.002) and less atopy (47% versus 58%, p=0.05), higher forced expiratory volume in 1 s (3.2 versus 2.8 L, p<0.001) and forced vital capacity (4.3 versus 3.9 L, p<0.001) compared with patients with severe asthma, who had higher blood (0.22×109 versus 0.17×109 cells·L−1, p=0.01) and sputum (3.0% versus 1.5%, p=0.01) eosinophils. Co-expression of all T2 biomarkers was a particular characteristic of severe asthma (p<0.001). In patients with eosinophilia, sputum eosinophilia without blood eosinophilia was present in 45% of patients with mild-to-moderate asthma and 35% with severe asthma. Conclusion Severe asthma is more commonly associated with activation of several T2 pathways, indicating that treatments targeting severe asthma may need to act more broadly on T2 inflammatory pathways. Implementation of airway inflammometry in clinical care is of paramount importance, as the best treatable trait is otherwise is overlooked in a large proportion of patients irrespective of disease severity.
|
|
| 6. |
- Geale, Kirk, et al.
(författare)
-
Late Breaking Abstract - NORdic Database for aSThmA Research (NORDSTAR) : Swedish and Finnish patients
- 2018
-
Ingår i: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 52
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: A cross-border research collaboration was recently initiated across the Nordic countries. These countries maintain population-based registers containing a variety of patient-level health and socioeconomic variables, providing a basis for nation-wide, longitudinal research.Aims and objectives: Describe key characteristics of Swedish and Finnish asthma populations in 2014.Methods: NORDSTAR is a research platform with ethical approval based on Nordic register data. Patients with an asthma diagnosis (ICD-10: J45/46) at any age in specialist care, or ≥2 dispensed respiratory prescriptions (ATC: R03) while aged 6-44, during 2004-2014 were included. Those with diagnosis and treatment pairs unlikely to be asthma were excluded. Demographics (age, sex, income, education level, and urban residence), treatment, comorbidities, and asthma specialist visits in 2014 were described using summary statistics.Results: Finnish comorbidity levels appeared higher than in Sweden. More Finnish patients filled OCS prescriptions (24%) than Swedish patients (20%). Most Swedish patients lived in an urban setting, and the distribution of education level was similar to the general population. Mean family income was 49,960 and 42,840 EUR in Sweden and Finland respectively, while 31% and 44% of patients visited an asthma specialist. Prevalence of asthma was highest among women in both countries, and age distributions were similar.Conclusions: NORDSTAR is a platform for conducting asthma outcomes research in the Nordics. Swedish and Finnish patients appear to be similar in many dimensions except for prevalence of asthma specialist care contacts.
|
|
| 7. |
- Gudbjartsson, Daniel F., et al.
(författare)
-
Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction
- 2009
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:3, s. 342-347
-
Tidskriftsartikel (refereegranskat)abstract
- Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).
|
|
| 8. |
- Heaney, Liam G., et al.
(författare)
-
Eosinophilic and Noneosinophilic Asthma : An Expert Consensus Framework to Characterize Phenotypes in a Global Real-Life Severe Asthma Cohort
- 2021
-
Ingår i: Chest. - : Elsevier BV. - 0012-3692. ; 160:3, s. 814-830
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Phenotypic characteristics of patients with eosinophilic and noneosinophilic asthma are not well characterized in global, real-life severe asthma cohorts. Research Question: What is the prevalence of eosinophilic and noneosinophilic phenotypes in the population with severe asthma, and can these phenotypes be differentiated by clinical and biomarker variables? Study Design and Methods: This was an historical registry study. Adult patients with severe asthma and available blood eosinophil count (BEC) from 11 countries enrolled in the International Severe Asthma Registry (January 1, 2015-September 30, 2019) were categorized according to likelihood of eosinophilic phenotype using a predefined gradient eosinophilic algorithm based on highest BEC, long-term oral corticosteroid use, elevated fractional exhaled nitric oxide, nasal polyps, and adult-onset asthma. Demographic and clinical characteristics were defined at baseline (ie, 1 year before or closest to date of BEC). Results: One thousand seven hundred sixteen patients with prospective data were included; 83.8% were identified as most likely (grade 3), 8.3% were identified as likely (grade 2), and 6.3% identified as least likely (grade 1) to have an eosinophilic phenotype, and 1.6% of patients showed a noneosinophilic phenotype (grade 0). Eosinophilic phenotype patients (ie, grades 2 or 3) showed later asthma onset (29.1 years vs 6.7 years; P < .001) and worse lung function (postbronchodilator % predicted FEV1, 76.1% vs 89.3%; P = .027) than those with a noneosinophilic phenotype. Patients with noneosinophilic phenotypes were more likely to be women (81.5% vs 62.9%; P = .047), to have eczema (20.8% vs 8.5%; P = .003), and to use anti-IgE (32.1% vs 13.4%; P = .004) and leukotriene receptor antagonists (50.0% vs 28.0%; P = .011) add-on therapy. Interpretation: According to this multicomponent, consensus-driven, and evidence-based eosinophil gradient algorithm (using variables readily accessible in real life), the severe asthma eosinophilic phenotype was more prevalent than previously identified and was phenotypically distinct. This pragmatic gradient algorithm uses variables readily accessible in primary and specialist care, addressing inherent issues of phenotype heterogeneity and phenotype instability. Identification of treatable traits across phenotypes should improve therapeutic precision.
|
|
| 9. |
- Hvidtfeldt, Morten, et al.
(författare)
-
Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes
- 2023
-
Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 152:1, s. 4-116
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation. Objective: We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment. Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (FENO) with a cutoff of 25 parts per billion. Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with FENO-high and FENO-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with FENO-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, −0.42; P = .04), and in those with FENO-low asthma, it correlated with the density in the airway smooth muscle (ρ, −0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33. Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with FENO-high asthma and with airway smooth muscle mast cells in patients with FENO-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
|
|
| 10. |
- Hvidtfeldt, Morten, et al.
(författare)
-
Bronchoscopic mucosal cryobiopsies as a method for studying airway disease
- 2019
-
Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 49:1, s. 27-34
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Investigating disease mechanisms and treatment responses in obstructive airway diseases with invasive sampling are hampered by the small size and mechanical artefacts that conventional forceps biopsies suffer from. Endoscopic cryobiopsies are larger and more intact and are being increasingly used. However, the technique has not yet been explored for obtaining mucosa biopsies. Objective: To investigate differences in size and quality of endobronchial mucosal biopsies obtained with cryotechnique and forceps. Further, to check for eligibility of cryobiopsies to be evaluated with immunohistochemistry and in situ hybridization and to investigate tolerability and safety of the technique. Methods: Endobronchial mucosal biopsies were obtained with cryotechnique and forceps from patients with haemoptysis undergoing bronchoscopy and evaluated by quantitative morphometry, automated immunohistochemistry and in situ hybridization. Results: A total of 40 biopsies were obtained from 10 patients. Cross-sectional areas were threefold larger in cryobiopsies (median: 3.08 mm2 (IQR: 1.79) vs 1.03 mm2 (IQR: 1.10), P < 0.001). Stretches of intact epithelium were 8-fold longer (median: 4.61 mm (IQR: 4.50) vs 0.55 mm (IQR: 1.23), P = 0.001). Content of glands (median: 0.095 mm2 (IQR: 0.30) vs 0.00 mm2 (IQR: 0.01), P = 0.002) and airway smooth muscle (median: 0.25 mm2 (IQR: 0.30) vs 0.060 mm2 (IQR: 0.11), P = 0.02) was higher in the cryobiopsies compared with forceps biopsies. Further, the cryobiopsies had well-preserved protein antigens and mRNA. Mild to moderate bleeding was the only complication observed. Conclusion and clinical relevance: By yielding significantly larger and more intact biopsies, the cryotechnique represents a valuable new research tool to explore the bronchi in airway disease. Ultimately with the potential to create better understanding of underlying disease mechanisms and improvement of treatments.
|
|
