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Sandström, Thomas
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Publications (10 of 152) Show all publications
Kuo, C.-H. S., Pavlidis, S., Zhu, J., Loza, M., Baribaud, F., Rowe, A., . . . Chung, K. F. (2019). Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET. Allergy. European Journal of Allergy and Clinical Immunology, 74(6), 1102-1112
Open this publication in new window or tab >>Contribution of airway eosinophils in airway wall remodeling in asthma: Role of MMP-10 and MET
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2019 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 6, p. 1102-1112Article in journal (Refereed) Published
Abstract [en]

Background Eosinophils play an important role in the pathophysiology of asthma being implicated in airway epithelial damage and airway wall remodeling. We determined the genes associated with airway remodeling and eosinophilic inflammation in patients with asthma. Methods We analyzed the transcriptomic data from bronchial biopsies of 81 patients with moderate-to-severe asthma of the U-BIOPRED cohort. Expression profiling was performed using Affymetrix arrays on total RNA. Transcription binding site analysis used the PRIMA algorithm. Localization of proteins was by immunohistochemistry. Results Using stringent false discovery rate analysis, MMP-10 and MET were significantly overexpressed in biopsies with high mucosal eosinophils (HE) compared to low mucosal eosinophil (LE) numbers. Immunohistochemical analysis confirmed increased expression of MMP-10 and MET in bronchial epithelial cells and in subepithelial inflammatory and resident cells in asthmatic biopsies. Using less-stringent conditions (raw P-value < 0.05, log2 fold change > 0.5), we defined a 73-gene set characteristic of the HE compared to the LE group. Thirty-three of 73 genes drove the pathway annotation that included extracellular matrix (ECM) organization, mast cell activation, CC-chemokine receptor binding, circulating immunoglobulin complex, serine protease inhibitors, and microtubule bundle formation pathways. Genes including MET and MMP10 involved in ECM organization correlated positively with submucosal thickness. Transcription factor binding site analysis identified two transcription factors, ETS-1 and SOX family proteins, that showed positive correlation with MMP10 and MET expression. Conclusion Pathways of airway remodeling and cellular inflammation are associated with submucosal eosinophilia. MET and MMP-10 likely play an important role in these processes.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
asthma, eosinophil, mast cell, MET, MMP10
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-161464 (URN)10.1111/all.13727 (DOI)000471068100007 ()30667542 (PubMedID)
Available from: 2019-07-09 Created: 2019-07-09 Last updated: 2019-07-09Bibliographically approved
diva2:1275689
Open this publication in new window or tab >>Effect and feasibility of non-linear periodized resistance training in people with COPD: study protocol for a randomized controlled trial
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2019 (English)In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 20, no 1, article id 6Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In people with chronic obstructive pulmonary disease (COPD), limb-muscle dysfunction is one of the most troublesome systemic manifestations of the disease, which at the functional level is evidenced by reduced strength and endurance of limb muscles. Improving limb-muscle function is an important therapeutic goal of COPD management, for which resistance training is recommended. However, current guidelines for resistance training in COPD mainly focus on improving muscle strength which only reflects one aspect of limb-muscle function and does not address the issue of reduced muscle endurance. The latter is of importance considering that the reduction in limb-muscle endurance often is greater than that of muscle weakness, and also, limb-muscle endurance seems to be closer related to walking capacity as well as arm function than to limb-muscle strength within this group of people. Thus, strategies targeting multiple aspects of the decreased muscle function are warranted to increase the possibility for an optimal effect for the individual patient. Periodized resistance training, which represents a planned variation of resistance training variables (i.e., volume, intensity, frequency, etc.), is one strategy that could be used to target limb-muscle strength as well as limb-muscle endurance within the same exercise regimen.

METHODS: This is an international, multicenter, randomized controlled trial comparing the effect and feasibility of non-linear periodized resistance training to traditional non-periodized resistance training in people with COPD. Primary outcomes are dynamic limb-muscle strength and endurance. Secondary outcomes include static limb-muscle strength and endurance, functional performance, quality of life, dyspnea, intramuscular adaptations as well as the proportion of responders. Feasibility of the training programs will be assessed and compared on attendance rate, duration, satisfaction, drop-outs as well as occurrence and severity of any adverse events.

DISCUSSION: The proposed trial will provide new knowledge to this research area by investigating and comparing the feasibility and effects of non-linear periodized resistance training compared to traditional non-periodized resistance training. If the former strategy produces larger physiological adaptations than non-periodized resistance training, this project may influence the prescription of resistance training in people with COPD.

TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03518723 . Registered on 13 April 2018.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Functional performance, Limb-muscle endurance, Limb-muscle strength, Pulmonary disease, chronic obstructive
National Category
Physiotherapy
Research subject
physiotherapy
Identifiers
urn:nbn:se:umu:diva-154980 (URN)10.1186/s13063-018-3129-y (DOI)000454906600006 ()30606240 (PubMedID)
Funder
Swedish Research Council, 2016-01802Swedish Heart Lung Foundation, E 127/16
Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-01-25Bibliographically approved
Perotin, J.-M., Schofield, J. P. R., Wilson, S. J., Ward, J., Brandsma, J., Strazzeri, F., . . . Djukanović, R. (2019). Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux [Letter to the editor]. European Respiratory Journal, 53(6), Article ID 1900453.
Open this publication in new window or tab >>Epithelial dysregulation in obese severe asthmatics with gastro-oesophageal reflux
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2019 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 53, no 6, article id 1900453Article in journal, Letter (Refereed) Published
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-161945 (URN)10.1183/13993003.00453-2019 (DOI)000474194800028 ()31023846 (PubMedID)
Available from: 2019-08-06 Created: 2019-08-06 Last updated: 2019-08-06Bibliographically approved
Jevnikar, Z., Ostling, J., Calven, J., Thorn, K., Israelsson, E., Oberg, L., . . . Olsson, H. (2019). Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation. Journal of Allergy and Clinical Immunology, 143(2), 577-590
Open this publication in new window or tab >>Epithelial IL-6 trans-signaling defines a new asthma phenotype with increased airway inflammation
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2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 2, p. 577-590Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Asthma, lung epithelium, transcriptomics, hierarchical clustering, IL-6 signaling, exacerbation frequency, eosinophils, airway inflammation, remodeling, epithelial integrity
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-162769 (URN)10.1016/j.jaci.2018.05.026 (DOI)000457718700018 ()29902480 (PubMedID)
Available from: 2019-09-05 Created: 2019-09-05 Last updated: 2019-09-05Bibliographically approved
Brinkman, P., Wagener, A. H., Hekking, P.-P., Bansal, A. T., Maitland-van der Zee, A.-H., Wang, Y., . . . Sterk, P. J. (2019). Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma. Journal of Allergy and Clinical Immunology, 143(5), 1811-1820.e7
Open this publication in new window or tab >>Identification and prospective stability of electronic nose (eNose)-derived inflammatory phenotypes in patients with severe asthma
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2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 143, no 5, p. 1811-1820.e7Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Electronic nose technology, exhaled breath, volatile organic compound, follow-up, severe asthma, unbiased clustering, eosinophils, neutrophils, oral corticosteroids
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-159403 (URN)10.1016/j.jaci.2018.10.058 (DOI)000466784600017 ()30529449 (PubMedID)
Available from: 2019-05-29 Created: 2019-05-29 Last updated: 2019-05-29Bibliographically approved
Backman, H., Jansson, S.-A., Stridsman, C., Eriksson, B., Hedman, L., Eklund, B.-M., . . . Rönmark, E. (2019). Severe asthma: A population study perspective. Clinical and Experimental Allergy, 49(6), 819-828
Open this publication in new window or tab >>Severe asthma: A population study perspective
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2019 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, no 6, p. 819-828Article in journal (Refereed) Published
Abstract [en]

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.

OBJECTIVE: To describe characteristics and estimate the prevalence of severe asthma in a large adult population-based asthma cohort followed for 10-28 years.

METHODS: N=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.

RESULTS: The 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 RELEVANCE: Severe 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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
IgE, asthma, eosinophils, epidemiology, lung function, neutrophils
National Category
Public Health, Global Health, Social Medicine and Epidemiology Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-157380 (URN)10.1111/cea.13378 (DOI)000475694600009 ()30817038 (PubMedID)
Available from: 2019-03-18 Created: 2019-03-18 Last updated: 2019-09-09Bibliographically approved
Tariq, K., Schofield, J. P., Nicholas, B. L., Burg, D., Brandsma, J., Bansal, A. T., . . . Djukanovic, R. (2019). Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma. Respiratory Medicine, 150, 66-73
Open this publication in new window or tab >>Sputum proteomic signature of gastro-oesophageal reflux in patients with severe asthma
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2019 (English)In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 150, p. 66-73Article in journal (Refereed) Published
Abstract [en]

Gastro-oesophageal reflux disease (GORD) has long been associated with poor asthma control without an established cause-effect relationship. 610 asthmatics (421 severe/88 mild-moderate) and 101 healthy controls were assessed clinically and a subset of 154 severe asthmatics underwent proteomic analysis of induced sputum using untargeted mass spectrometry, LC-IMS-MSE. Univariate and multiple logistic regression analyses (MLR) were conducted to identify proteins associated with GORD in this cohort. When compared to mild/moderate asthmatics and healthy individuals, respectively, GORD was three-and ten-fold more prevalent in severe asthmatics and was associated with increased asthma symptoms and oral corticosteroid use, poorer quality of life, depression/anxiety, obesity and symptoms of sino-nasal disease. Comparison of sputum proteomes in severe asthmatics with and without active GORD showed five differentially abundant proteins with described roles in antimicrobial defences, systemic inflammation and epithelial integrity. Three of these were associated with active GORD by multiple linear regression analysis: Ig lambda variable 1-47 (p = 0.017) and plasma protease C1 inhibitor (p = 0.043), both in lower concentrations, and lipocalin-1 (p = 0.034) in higher concentrations in active GORD. This study provides evidence which suggests that reflux can cause subtle perturbation of proteins detectable in the airways lining fluid and that severe asthmatics with GORD may represent a distinct phenotype of asthma.

Place, publisher, year, edition, pages
Saunders Elsevier, 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-158738 (URN)10.1016/j.rmed.2019.02.008 (DOI)000463627700010 ()30961953 (PubMedID)
Available from: 2019-05-21 Created: 2019-05-21 Last updated: 2019-05-21Bibliographically approved
Schofield, J. P. R., Burg, D., Nicholas, B., Strazzeri, F., Brandsma, J., Staykova, D., . . . Wecksell, P.-A. (2019). Stratification of asthma phenotypes by airway proteomic signatures. Journal of Allergy and Clinical Immunology, 144(1), 70-82
Open this publication in new window or tab >>Stratification of asthma phenotypes by airway proteomic signatures
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2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 144, no 1, p. 70-82Article in journal (Refereed) Published
Abstract [en]

Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms.

Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification.

Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms.

Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysisidentified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms.

Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Asthma, proteomics, biomarkers, eosinophils, neutrophils
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-161709 (URN)10.1016/j.jaci.2019.03.013 (DOI)000473432800011 ()30928653 (PubMedID)
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-08-05Bibliographically approved
Simpson, A. J., Hekking, P.-P., Shaw, D. E., Fleming, L. J., Roberts, G., Riley, J. H., . . . Fowler, S. J. (2019). Treatable traits in the European U-BIOPRED adult asthma cohorts. Allergy. European Journal of Allergy and Clinical Immunology, 74(2), 406-411
Open this publication in new window or tab >>Treatable traits in the European U-BIOPRED adult asthma cohorts
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2019 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 74, no 2, p. 406-411Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Wiley, 2019
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-157477 (URN)10.1111/all.13629 (DOI)000458896800026 ()30307629 (PubMedID)
Available from: 2019-03-22 Created: 2019-03-22 Last updated: 2019-03-22Bibliographically approved
Farooqi, N., Carlsson, M., Håglin, L., Sandström, T. & Slinde, F. (2018). Energy expenditure in women and men with COPD. Clinical Nutrition ESPEN, 28, 171-178
Open this publication in new window or tab >>Energy expenditure in women and men with COPD
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2018 (English)In: Clinical Nutrition ESPEN, ISSN 2405-4577, Vol. 28, p. 171-178Article in journal (Refereed) Published
Abstract [en]

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. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Energy expenditure in COPD, Doubly labeled water and COPD, FEV1 and energy expenditure
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-153541 (URN)10.1016/j.clnesp.2018.08.008 (DOI)000448887100025 ()30390877 (PubMedID)
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2019-08-21Bibliographically approved
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