Raised sputum extracellular DNA confers lung function impairment and poor symptom control in an exacerbation-susceptible phenotype of neutrophilic asthma

Respiratory Research

Thomas Bahmer¹  Gesine Hansen²  Matthias Kopp³  Frederik Trinkmann⁴  Erika von Mutius⁵  Olaf Holz⁶  Klaus F. Rabe⁷  Mustafa Abdo⁷  Frauke Pedersen⁸  Henrik Watz⁹  Anne-Marie Kirsten⁹  Torsten Goldmann^1,10  Sebastian Marwitz^1,10  Mohib Uddin^1,11 

[1] Department for Internal Medicine I, Airway Research Center North (ARCN), German Center for Lung Research (DZL), University Hospital Schleswig-Holstein-Campus Kiel, Kiel, Germany;Department of Paediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Biomedical Research in Endstage and Obstructive Lung Disease (BREATH), German Center for Lung Research (DZL), Hannover, Germany;Department of Pediatric Pneumology, Inselspital, University Children’s Hospital of Bern, University of Bern, Bern, Switzerland;Division of Pediatric Pneumology and Allergology, University Hospital Schleswig-Holstein-Campus Luebeck, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Luebeck, Germany;Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany;Department of Biomedical Informatics, Heinrich-Lanz-Center, University Medical Center Mannheim, Mannheim, Germany;Dr Von Hauner Children’s Hospital, Ludwig Maximilians University of Munich, Comprehensive Pneumology Center Munich (CPC-M), German Center for Lung Research (DZL), Munich, Germany;Fraunhofer ITEM, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research, Hannover, Germany;LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, 22927, Grosshansdorf, Germany;LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Wöhrendamm 80, 22927, Grosshansdorf, Germany;Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany;Pulmonary Research Institute at the LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, Germany;Research Center Borstel, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Borstel, Germany;Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;

关键词: Extracellular DNA;    Neutrophil extracellular traps;    Neutrophilic asthma;    Asthma outcomes;   

DOI  :  10.1186/s12931-021-01759-z

来源: Springer

【 摘 要 】

BackgroundExtracellular DNA (e-DNA) and neutrophil extracellular traps (NETs) are linked to asthmatics airway inflammation. However, data demonstrating the characterization of airway inflammation associated with excessive e-DNA production and its impact on asthma outcomes are limited.ObjectiveTo characterize the airway inflammation associated with excessive e-DNA production and its association with asthma control, severe exacerbations and pulmonary function, particularly, air trapping and small airway dysfunction.MethodsWe measured e-DNA concentrations in induced sputum from 134 asthma patients and 28 healthy controls. We studied the correlation of e-DNA concentrations with sputum neutrophils, eosinophils and macrophages and the fractional exhaled nitric oxide (FeNO). Lung function was evaluated using spirometry, body plethysmography, impulse oscillometry and inert gas multiple breath washout. We stratified patients with asthma into low-DNA and high-DNA to compare lung function impairments and asthma outcomes.ResultsPatients with severe asthma had higher e-DNA concentration (54.2 ± 42.4 ng/µl) than patients with mild-moderate asthma (41.0 ± 44.1 ng/µl) or healthy controls (26.1 ± 16.5 ng/µl), (all p values < 0.05). E-DNA concentrations correlated directly with sputum neutrophils (R = 0.49, p < 0.0001) and negatively with sputum macrophages (R = − 0.36, p < 0.0001), but neither with sputum eosinophils (R = 0.10, p = 0.26), nor with FeNO (R = − 0.10, p = 0.22). We found that 29% of asthma patients (n = 39) had high e-DNA concentrations above the upper 95th percentile value in healthy controls (55.6 ng /μl). High-DNA was associated with broad lung function impairments including: airflow obstruction of the large (FEV1) and small airways (FEF50%, FEF25–75), increased air trapping (RV, RV/TLC), increased small airway resistance (R5-20, sReff), decreased lung elasticity (X5Hz) and increased ventilation heterogeneity (LCI), (all P values < 0.05). We also found that high e-DNA was associated with nearly three-fold greater risk of severe exacerbations (OR 2·93 [95% CI 1.2–7.5]; p = 0·012), worse asthma control test (p = 0.03), worse asthma control questionnaire scores (p = 0.01) and higher doses of inhaled corticosteroids (p = 0.026).ConclusionIncreased production of extracellular DNA in the airway characterizes a subset of neutrophilic asthma patients who have broad lung function impairments, poor symptom control and increased risk of severe exacerbations.

【 授权许可】

CC BY