Abstract
Detection and quantification of microRNAs (miRNAs) in exhaled breath condensate (EBC) has been poorly explored. Therefore we aimed to assess miRNAs in EBC as potential biomarkers to diagnose and endotype asthma in school aged children. In a cross sectional, nested case control study, all the asthmatic children (n = 71) and a random sample of controls (n = 115), aged 7 to 12 years, attending 71 classrooms from 20 local schools were selected and arbitrarily allocated to the development or validation set. Participants underwent skin-prick testing, spirometry with bronchodilation, had exhaled level of nitric oxide determined and EBC collected. Based on previous studies eleven miRNAs were chosen and analyzed in EBC by reverse transcription-quantitative real-time PCR. Principal component analysis was applied to identify miRNAs profiles and associations were estimated using regression models. In the development set (n = 89) two clusters of miRNAs were identified. After adjustments, cluster 1 and three of its clustered miRNAs, miR-126-3p, miR-133a-3p and miR-145-5p were positively associated with asthma. Moreover miR-21-5p was negatively associated with symptomatic asthma and positively associated with positive bronchodilation without symptoms. An association was also found between miR-126-3p, cluster 2 and one of its clustered miRNA, miR-146-5p, with higher FEF25-75 reversibility. These findings were confirmed in the validation set (n = 97) where two identical clusters of miRNAs were identified. Additional significant associations were observed between miR-155-5p with symptomatic asthma, negative bronchodilation with symptoms and positive bronchodilation without symptoms. We showed that microRNAs can be measured in EBC of children and may be used as potential biomarkers of asthma, assisting asthma endotype establishment.
Highlights
Pediatric asthma is a highly-prevalent heterogeneous disease characterized by variable airflow obstruction with cough, dyspnea and wheezing
Our study showed that miRNAs can be measured in exhaled breath condensate of school aged children and may be used as potential biomarkers of asthma, assisting asthma endotype establishment
The analysis of miRNAs by principal component analysis revealed the existence of two clusters, one of them associated with children with asthma defined by positive bronchodilation or self-reported medical diagnosis with reported symptoms in the previous year and the other with higher small airways response to salbutamol
Summary
Pediatric asthma is a highly-prevalent heterogeneous disease characterized by variable airflow obstruction with cough, dyspnea and wheezing. Asthma is described in terms of disease phenotypes, since phenotypic characteristics may be recognizable. In this context, the term endotype was created to cluster asthmatics by their phenotypical characteristics and by the pathophysiological features of the disease [1] and may explain the clinical presentation, epidemiology, and response to different treatments. Most of asthma biomarkers used for clinical purposes are sampled in blood, exhaled breath, or urine. Collection of exhaled breath condensate (EBC) is simple, safe, non-invasive and highly repeatable, and potentially allows the assessment of biomarkers of airway inflammation, being increasingly used as a tool for biomarker discovery [2]. It is essential to improve biomarkers diagnostic accuracy to introduce them into clinical practice
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