| 1. |
- Brinkman, Paul, et al.
(author)
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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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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:5, s. 1811-1820.e7
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Journal article (peer-reviewed)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. |
- von Büllow, A., et al.
(author)
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Severe asthma trajectories in adults: findings from the NORDSTAR cohort
- 2023
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In: European Respiratory Journal. - : European Respiratory Society. - 0903-1936 .- 1399-3003. ; 62:3
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Journal article (peer-reviewed)abstract
- Background There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma.Methods We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018.Results Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma.Conclusions Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma.
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| 3. |
- Östling, Jörgen, et al.
(author)
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IL-17-high asthma with features of a psoriasis immunophenotype
- 2019
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In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 144:5, s. 1198-1213
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Journal article (peer-reviewed)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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| 4. |
- Eklund, Linda, et al.
(author)
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An experimental exposure study revealing composite airway effects of physical exercise in a subzero environment
- 2021
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In: International Journal of Circumpolar Health. - : Taylor & Francis. - 1239-9736 .- 2242-3982. ; 80:1
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Journal article (peer-reviewed)abstract
- Exposure to a cold climate is associated with an increased morbidity and mortality, but the specific mechanisms are largely unknown. People with cardiopulmonary disease and winter endurance athletes are particularly vulnerable. This study aimed to map multiple domains of airway responses to exercise in subzero temperature in healthy individuals.Thirty-one healthy subjects underwent whole-body exposures for 50 minutes on two occasions in an environmental chamber with intermittent moderate-intensity exercise in +10 °C and -10 °C. Lung function, plasma/urine CC16 , and symptoms were investigated before and after exposures.Compared to baseline, exercise in -10 °C decreased FEV1 (p=0.002), FEV1/FVC (p<0.001), and increased R20Hz (p=0.016), with no differences between exposures. Reactance increased after +10 °C (p=0.005), which differed (p=0.042) from a blunted response after exercise in -10 °C. Plasma CC16 increased significantly within exposures, without differences between exposures. Exercise in -10 °C elicited more intense symptoms from the upper airways, compared to +10 °C. Symptoms from the lower airways were few and mild. Short-duration moderate-intensity exercise in -10 °C induces mild symptoms from the lower airways, no lung function decrements or enhanced leakage of biomarkers of airway epithelial injury, and no peripheral bronchodilatation, compared to exercise in +10 °C.
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| 5. |
- Backman, Helena, et al.
(author)
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Severe asthma : A population study perspective
- 2019
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In: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 49:6, s. 819-828
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Journal article (peer-reviewed)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. |
- Eklund, Linda M., et al.
(author)
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Cold air exposure at -15 °C induces more airway symptoms and epithelial stress during heavy exercise than rest without aggravated airway constriction
- 2022
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In: European Journal of Applied Physiology. - : Springer. - 1439-6319 .- 1439-6327. ; 122:12, s. 2533-2544
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Journal article (peer-reviewed)abstract
- Purpose: Exposure to cold air may harm the airways. It is unclear to what extent heavy exercise adds to the cold-induced effects on peripheral airways, airway epithelium, and systemic immunity among healthy individuals. We investigated acute effects of heavy exercise in sub-zero temperatures on the healthy airways.Methods: Twenty-nine healthy individuals underwent whole body exposures to cold air in an environmental chamber at − 15 °C for 50 min on two occasions; a 35-min exercise protocol consisting of a 5-min warm-up followed by 2 × 15 min of running at 85% of VO2max vs. 50 min at rest. Lung function was measured by impulse oscillometry (IOS) and spirometry before and immediately after exposures. CC16 in plasma and urine, and cytokines in plasma were measured before and 60 min after exposures. Symptoms were surveyed pre-, during and post-trials.Results: FEV1 decreased after rest (− 0.10 ± 0.03 L, p < 0.001) and after exercise (− 0.06 ± 0.02 L, p = 0.012), with no difference between trials. Exercise in − 15 °C induced greater increases in lung reactance (X5; p = 0.023), plasma CC16 (p < 0.001) as well as plasma IL-8 (p < 0.001), compared to rest. Exercise induced more intense symptoms from the lower airways, whereas rest gave rise to more general symptoms.Conclusion: Heavy exercise during cold air exposure at − 15 °C induced signs of an airway constriction to a similar extent as rest in the same environment. However, biochemical signs of airway epithelial stress, cytokine responses, and symptoms from the lower airways were more pronounced after the exercise trial.
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| 7. |
- Jevnikar, Z., et al.
(author)
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Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
- 2019
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In: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 143:2, s. 577-590
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Journal article (peer-reviewed)abstract
- Background: 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. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: 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. Results: 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 1 beta, IL-8, and IL-1 beta. Conclusions: 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.
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| 8. |
- Backman, Helena, et al.
(author)
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Determinants of severe asthma : a long-term cohort study in northern Sweden
- 2022
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In: Journal of Asthma and Allergy. - : Dove press. - 1178-6965. ; 15, s. 1429-1439
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Journal article (peer-reviewed)abstract
- Background: Risk factors for severe asthma are not well described. The aim was to identify clinical characteristics and risk factors at study entry that are associated with severe asthma at follow-up in a long-term prospective population-based cohort study of adults with asthma.Methods: Between 1986 and 2001, 2055 adults with asthma were identified by clinical examinations of population-based samples in northern Sweden. During 2012–2014, n = 1006 (71% of invited) were still alive, residing in the study area and participated in a follow-up, of which 40 were identified as having severe asthma according to ERS/ATS, 131 according to GINA, while 875 had other asthma. The mean follow-up time was 18.7 years.Results: Obesity at study entry and adult-onset asthma were associated with severe asthma at follow-up. While severe asthma was more common in those with adult-onset asthma in both men and women, the association with obesity was observed in women only. Sensitization to mites and moulds, but not to other allergens, as well as NSAID-related respiratory symptoms was more common in severe asthma than in other asthma. Participants with severe asthma at follow-up had lower FEV1, more pronounced FEV1 reversibility, and more wheeze, dyspnea and nighttime awakenings already at study entry than those with other asthma.Conclusion: Adult-onset asthma is an important risk factor for development of severe asthma in adults, and obesity increased the risk among women. The high burden of respiratory symptoms already at study entry also indicate long-term associations with development of severe asthma.
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| 9. |
- Backman, Helena, et al.
(author)
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FEV1 decline in relation to blood eosinophils and neutrophils in a population-based asthma cohort
- 2020
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In: World Allergy Organization Journal. - : Elsevier. - 1939-4551. ; 13:3
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Journal article (peer-reviewed)abstract
- Background: The relationship between lung function decline and eosinophils and neutrophils has important therapeutic implications among asthmatics, but it has rarely been studied in large cohort studies.Objective: The aim is to study the relationship between blood eosinophils and neutrophils and FEV1 decline in a long-term follow-up of a population-based adult asthma cohort.Methods: In 2012-2014, an adult asthma cohort was invited to a follow-up including spirometry, blood sampling, and structured interviews, and n = 892 participated (55% women, mean age 59 y, 32-92 y). Blood eosinophils, neutrophils and FEV 1 decline were analyzed both as continuous variables and divided into categories with different cut-offs. Regression models adjusted for smoking, exposure to vapors, gas, dust, or fumes (VGDF), use of inhaled and oral corticosteroids, and other possible confounders were utilized to analyze the relationship between eosinophils and neutrophils at follow-up and FEV1 decline.Results: The mean follow-up time was 18 years, and the mean FEV 1 decline was 27 ml/year. The annual FEV1 decline was related to higher levels of both blood eosinophils and neutrophils at follow-up, but only the association with eosinophils remained when adjusted for confounders. Further, the association between FEV1 decline and eosinophils was stronger among those using ICS. With EOS <0.3 × 109/L as reference, a more rapid decline in FEV1 was independently related to EOS ≥0.4 × 109/L in adjusted analyses.Conclusions and clinical relevance: Besides emphasizing the importance of smoking cessation and reduction of other harmful exposures, our real-world results indicate that there is an independent relationship between blood eosinophils and FEV1 decline among adults with asthma.
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| 10. |
- Farooqi, Nighat, 1969-, et al.
(author)
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Energy expenditure in women and men with COPD
- 2018
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In: Clinical Nutrition Espen. - : Elsevier BV. - 2405-4577. ; 28, s. 171-178
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Journal article (peer-reviewed)abstract
- Background: Many patients with chronic obstructive pulmonary disease (COPD) lose weight. Successful nutritional intervention is vital, thus assessment of energy requirement is required. The aim of this study was to present an improved possibility to assess energy requirement in patients with COPD. Methods: Pub Med search was conducted for all the studies reporting total energy expenditure (TEE) measured by doubly labeled water (DLW) method in patients with COPD. Four studies were identified, whereof three were conducted in Sweden. The present analysis is based on these three studies of which the data was acquired. Results: There was a large variation in resting metabolic rate (RMR) and TEE. Body mass index decreased significantly with increase in disease severity (p < .001), and correlated significantly to forced expiratory volume in 1 s (FEV1) % predicted (r = .627, p < .001). FEV1% predicted had a significant correlation with RMR/kg body weight (BW)/day (r = -.503, p = .001), RMR/kg fat-free mass (FFM)/day (r = .338, p = .031), and TEE/kg FFM/day (r = .671, p < .001). Compared to men, women had a lower RMR and TEE/kg BW/day (p < .001 respectively p = .002), and higher RMR and TEE/kg FFM/day (p = .080 respectively p = .005). The correlates of: RMR/kg BW were gender and FEV1% predicted; of TEE/kg BW the correlates were age and gender, and of TEE/kg FFM the correlates were age and FEV1% predicted. Conclusion: In this study, we have presented a possibility to assess energy requirement per kg BW/day and per kg FFM/day in patients with COPD in clinical settings. However, gender, age, and disease severity must be considered. (C) 2018 The Authors. Published by Elsevier Ltd on behalf of European Society for Clinical Nutrition and Metabolism.
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