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Fixed airflow obstruction relates to eosinophil activation in asthmatics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.ORCID iD: 0000-0002-0198-2718
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.ORCID iD: 0000-0003-0784-0443
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2019 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, no 2, p. 155-162Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Some asthmatics develop irreversible chronic airflow obstruction, for example, fixed airflow obstruction (fixed-AO). This is probably a consequence of airway remodelling, but neither its relation to inflammation nor which asthma biomarkers can be clinically useful are elucidated. We hypothesized that the presence of type 2 inflammation relates to fixed-AO.

OBJECTIVES: To evaluate the presence of four markers for type 2 inflammation in fixed airflow obstruction among asthmatics.

METHODS: This was a cross-sectional study of 403 participants with asthma, aged 17-75 years, from three Swedish centres. Fixed airflow obstruction was defined as forced expiratory volume during the first second (FEV1 ) over forced vital capacity (FVC) being below the lower limit of normal (LLN). The following type 2 inflammation markers were assessed: exhaled nitric oxide (FeNO), serum periostin, serum eosinophil cationic protein (S-ECP), and urinary eosinophil-derived neurotoxin (U-EDN).

RESULTS: Elevated U-EDN (values in the highest tertile, ≥65.95 mg/mol creatinine) was more common in subjects with fixed-AO vs. subjects without fixed-AO: 55% vs. 29%, P < 0.001. Elevated U-EDN related to increased likelihood of having fixed-AO in both all subjects and never-smoking subjects, with adjusted (adjusted for sex, age group, use of inhaled corticosteroids last week, atopy, early-onset asthma, smoking history, and packyears) odds ratios (aOR) of 2.38 (1.28-4.41) and 2.51 (1.04-6.07), respectively. In a separate analysis, having both elevated S-ECP (>20 μg/L) and U-EDN was related to having the highest likelihood of fixed-AO (aOR (95% CI) 6.06 (2.32-15.75)). Elevated serum periostin or FeNO did not relate to fixed-AO.

CONCLUSIONS AND CLINICAL RELEVANCE: These findings support that type 2 inflammation, and in particular eosinophil inflammation, is found in asthma with fixed-AO. This could indicate a benefit from eosinophil-directed therapies. Further longitudinal studies are warranted to investigate causality and relation to lung function decline.

Place, publisher, year, edition, pages
2019. Vol. 49, no 2, p. 155-162
National Category
Medical and Health Sciences Immunology in the medical area
Research subject
Clinical Physiology
Identifiers
URN: urn:nbn:se:uu:diva-372784DOI: 10.1111/cea.13302ISI: 000457469600003PubMedID: 30365193OAI: oai:DiVA.org:uu-372784DiVA, id: diva2:1276825
Funder
Swedish Heart Lung FoundationSwedish Research CouncilVårdal FoundationStockholm County CouncilSwedish Asthma and Allergy AssociationSwedish Foundation for Strategic Research Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2020-03-04Bibliographically approved
In thesis
1. Inflammation in asthma: relation to symptomatology, exacerbations and lung function
Open this publication in new window or tab >>Inflammation in asthma: relation to symptomatology, exacerbations and lung function
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Asthma is an inflammatory disease in the airways. It is characterized by respiratory symptoms such as wheezing, variable airflow obstruction and impaired lung function development. A better understanding of the underlying inflammation is crucial in order to treat and prevent asthma symptoms and lung function deterioration.

We have evaluated six inflammatory markers in relation to asthma symptoms, asthma attacks, and lung function measures (fixed airflow obstruction (FAO) and lung function development over time) in five investigations. The markers (elevated levels) were fraction of exhaled NO (FeNO) (elevated ≥25ppb), serum eosinophil cationic protein (S-ECP) (≥20 µg/L), blood eosinophils (B-Eos) (≥300 cells/µL), urinary eosinophil derived neurotoxin (U-EDN) (≥65.95mg/mol creatinine), serum periostin (S-periostin) ( ≥74μg/L), and blood neutrophils (B-Neu) (≥5,100 cells/µL).  The studied populations consisted of mainly adults (except in Paper II) and included asthmatics from the Swedish part of the Global Allergy and Asthma European Network survey (Papers I and III), the American National Health and Nutrition Examination Survey (Papers II and IV), the Uppsala part of the European Community Respiratory Health Survey I-III, the Vlagtwedde and Vlaardingen study, and the Rotterdam study, the latter two from the Netherlands (Paper V). All study populations were population based, and the asthmatics included had mainly mild to moderately severe asthma.

The main findings are that simultaneously elevated FeNO and S-ECP are associated with more reported asthma symptoms and attacks, and elevated FeNO and B-Eos are associated with lower lung function, suggesting a value in measuring both local (FeNO) and systemic (S-ECP, B-Eos) inflammation in asthma. Eosinophil inflammation (elevated U-EDN and S-ECP) was associated with FAO in asthma, while the other type-2 markers FeNO and S-periostin were not. Elevated B-Eos was further associated to lower lung function measures in a general population, and a faster lung function decline in asthmatics. FeNO was more often elevated in asthmatics, but was difficult to robustly associate to a specific disease characteristic. B-Neu was associated to FAO in participants with current smoking or pronounced smoking history.

In conclusion, asthma with elevated markers for eosinophil inflammation was associated to worse morbidity and lung function development in comparison with asthmatics without elevated markers for eosinophil inflammation. These results indicate ongoing eosinophil inflammation in asthma as closely associated to disease activity and the absence of eosinophil inflammation to less morbidity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 88
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1645
Keywords
Asthma, eosinophil, eosinophil cationic protein, eosinophil derived neurotoxin, periostin, neutrophil, fixed airflow obstruction, lung function, asthma attack, asthma symptom
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:uu:diva-406074 (URN)978-91-513-0890-6 (ISBN)
Public defence
2020-04-24, H:son Holmdahlsalen, Akademiska Sjukhuset, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2020-04-01 Created: 2020-03-04 Last updated: 2020-05-19

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Mogensen, IdaAlving, KjellVenge, PerBorres, Magnus P.Janson, ChristerMalinovschi, Andrei

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