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Sandström, Thomas
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Selley, L., Schuster, L., Marbach, H., Forsthuber, T., Forbes, B., Gant, T. W., . . . Kumar, A. (2020). Brake dust exposure exacerbates inflammation and transiently compromises phagocytosis in macrophages. Metallomics, 12(3), 371-386
Open this publication in new window or tab >>Brake dust exposure exacerbates inflammation and transiently compromises phagocytosis in macrophages
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2020 (English)In: Metallomics, ISSN 1756-5901, E-ISSN 1756-591X, Vol. 12, no 3, p. 371-386Article in journal (Refereed) Published
Abstract [en]

Studies have emphasised the importance of combustion-derived particles in eliciting adverse health effects, especially those produced by diesel vehicles. In contrast, few investigations have explored the potential toxicity of particles derived from tyre and brake wear, despite their significant contributions to total roadside particulate mass. The objective of this study was to compare the relative toxicity of compositionally distinct brake abrasion dust (BAD) and diesel exhaust particles (DEP) in a cellular model that is relevant to human airways. Although BAD contained considerably more metals/metalloids than DEP (as determined by inductively coupled plasma mass spectrometry) similar toxicological profiles were observed in U937 monocyte-derived macrophages following 24 h exposures to 4–25 μg ml−1 doses of either particle type. Responses to the particles were characterised by dose-dependent decreases in mitochondrial depolarisation (p ≤ 0.001), increased secretion of IL-8, IL-10 and TNF-α (p ≤ 0.05 to p ≤ 0.001) and decreased phagocytosis of S. aureus (p ≤ 0.001). This phagocytic deficit recovered, and the inflammatory response resolved when challenged cells were incubated for a further 24 h in particle-free media. These responses were abrogated by metal chelation using desferroxamine. At minimally cytotoxic doses both DEP and BAD perturbed bacterial clearance and promoted inflammatory responses in U937 cells with similar potency. These data emphasise the requirement to consider contributions of abrasion particles to traffic-related clinical health effects.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2020
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-170560 (URN)10.1039/c9mt00253g (DOI)000527735100005 ()31915771 (PubMedID)
Available from: 2020-05-11 Created: 2020-05-11 Last updated: 2020-05-11Bibliographically approved
Backman, H., Lindberg, A., Hedman, L., Stridsman, C., Jansson, S.-A., Sandström, T., . . . Rönmark, E. (2020). FEV1 decline in relation to blood eosinophils and neutrophils in a population-based asthma cohort. The World Allergy Organization journal, 13(3), Article ID 100110.
Open this publication in new window or tab >>FEV1 decline in relation to blood eosinophils and neutrophils in a population-based asthma cohort
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2020 (English)In: The World Allergy Organization journal, ISSN 1939-4551, Vol. 13, no 3, article id 100110Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
ANOVA, Analysis of variance, ATS, American Thoracic Society, Asthma, BMI, Body mass index, Cohort, ECRHS, European Community Respiratory Health Survey, EOS, Eosinophils, ERS, European Respiratory Society, Eosinophils, FEV1, FEV1, Forced Expiratory Volume in 1 s, FEV1pp, FEV1 percent of predicted, FVC, Forced Expiratory Volume, GLI, Global Lung function Initiative, ICS, Inhaled corticosteroids, IgE, Immunoglobulin E, L, Liters, Ml, Milliliters, N, Number, NEU, Neutrophils, Neutrophils, OCS, Oral corticosteroids, OLIN, Obstructive Lung Disease in Northern Sweden, OLS, Ordinary Least Squares, VGDF, Vapors, gas, dust or fumes
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-169223 (URN)10.1016/j.waojou.2020.100110 (DOI)32206161 (PubMedID)
Funder
Swedish Heart Lung FoundationSwedish Research CouncilVästerbotten County CouncilNorrbotten County CouncilSwedish Asthma and Allergy AssociationVisare Norr
Available from: 2020-03-26 Created: 2020-03-26 Last updated: 2020-03-27Bibliographically approved
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
Frykholm, E., Klijn, P., Saey, D., van Hees, H. W. H., Stål, P., Sandström, T., . . . Nyberg, A. (2019). Effect and feasibility of non-linear periodized resistance training in people with COPD: study protocol for a randomized controlled trial. Trials, 20(1), Article ID 6.
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: 2020-05-15Bibliographically 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: 2020-05-15Bibliographically approved
Pourazar, J., Sehlstedt, M., Rankin, G., Uski, O., Boman, C., Lopez, N., . . . Muala, A. (2019). Exposure to wood smoke induced activation of lymphocyte subtypes in peripheral blood. Paper presented at European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.. European Respiratory Journal, 54
Open this publication in new window or tab >>Exposure to wood smoke induced activation of lymphocyte subtypes in peripheral blood
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2019 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Sheffield: European Respiratory Society Journals, 2019
Keywords
Air pollution, Systemic effect, Inflammation
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-168164 (URN)10.1183/13993003.congress-2019.PA1983 (DOI)000507372402143 ()
Conference
European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.
Note

Supplement: 63. Meeting Abstract: PA1983.

Available from: 2020-03-17 Created: 2020-03-17 Last updated: 2020-03-17Bibliographically 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
Östling, J., van Geest, M., Schofield, J. P. R., Jevnikar, Z., Wilson, S., Ward, J., . . . Wilson, S. J. (2019). IL-17-high asthma with features of a psoriasis immunophenotype. Journal of Allergy and Clinical Immunology, 144(5), 1198-1213
Open this publication in new window or tab >>IL-17-high asthma with features of a psoriasis immunophenotype
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2019 (English)In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 144, no 5, p. 1198-1213Article in journal (Refereed) Published
Abstract [en]

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 IL1BIL6IL8, 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.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
IL-17, asthma, bronchial biopsies, bronchial brushings, biomarkers, psoriasis
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-165356 (URN)10.1016/j.jaci.2019.03.027 (DOI)000495004700013 ()30998987 (PubMedID)
Available from: 2019-11-25 Created: 2019-11-25 Last updated: 2020-05-15Bibliographically approved
Sjöström, R., Söderström, L., Klockmo, C., Patrician, A., Sandström, T., Björklund, G., . . . Stenfors, N. (2019). Qualitative identification and characterisation of self-reported symptoms arising in humans during experimental exposure to cold air. International Journal of Circumpolar Health, 78(1), Article ID 1583528.
Open this publication in new window or tab >>Qualitative identification and characterisation of self-reported symptoms arising in humans during experimental exposure to cold air
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2019 (English)In: International Journal of Circumpolar Health, ISSN 1239-9736, E-ISSN 2242-3982, Vol. 78, no 1, article id 1583528Article in journal (Refereed) Published
Abstract [en]

Background: Exposure to cold air is associated with increased morbidity and mortality in the general population. It is difficult to study the effects of whole-body exposure to cold air under controlled conditions in real life. Objectives: The aim of this study was to (1) explore and describe the experience of symptoms in humans during experimental and controlled exposures to cold air, by using controlled environmental chamber exposures and qualitative methodology, and to (2) categorise the symptoms. Method: The study used a randomised, double blind design, in which 34 subjects undertook rest and moderate-intensity exercise in an environmental chamber set to two or three different temperatures (0, -10, and -17 degrees C) on separate occasions. During the chamber exposures, subjects were interviewed. Qualitative content analysis was selected as the method of analysis. Findings: Subjects reported 50 distinct symptoms during the exposures. The symptoms were grouped into ten sub-categories and two major categories; airway versus whole-body symptoms. Conclusion: We have identified a broad range of symptoms in humans undertaking rest and moderate-intensity exercise at sub-zero temperatures. The symptoms and their categories may well be used to more extensively and quantitatively map cold-induced morbidity.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Cold temperature, environmental chamber, healthy, physical activity, qualitative analysis, respiratory sease
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-157608 (URN)10.1080/22423982.2019.1583528 (DOI)000459975500001 ()30821652 (PubMedID)
Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2020-05-18Bibliographically approved
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