Rationale Asthma is characterised by inflammation and reversible airway obstruction However, these features are not always closely related Fluctuations of daily lung function contain information on asthma phenotypes, exacerbation risk and response to long-acting-agonists Objectives In search of subgroups of asthmatic participants with specific lung functional features, we developed and validated a novel clustering approach to asthma phenotyping, which exploits the information contained within the fluctuating behaviour of twice-daily lung function measurements Methods Forced expiratory volume during the first second (FEV1) and peak expiratory flow (PEF) were prospectively measured over 4 weeks in 696 healthy and asthmatic school children (Protection Against Allergy- Study in Rural Environments (PASTURE)/EFRAIM cohort), and over 1year in 138 asthmatic adults with mild-to-moderate or severe asthma (Pan-European Longitudinal Assessment of Clinical Course and BIOmarkers in Severe Chronic AIRway Disease (BIOAIR) cohort) Using enrichment analysis, we explored whether the method identifies clinically meaningful, distinct clusters of participants with different lung functional fluctuation patterns Measurements and main results In the PASTURE/EFRAIM dataset, we found four distinct clusters Two clusters were enriched in children with well-known clinical characteristics of asthma In cluster 3, children from a farming environment predominated, whereas cluster 4 mainly consisted of healthy controls About 79% of cluster 3 carried the asthma-risk allele rs7216389 of the 17q21 locus In the BIOAIR dataset, we found two distinct clusters clearly discriminating between individuals with mild-to-moderate and severe asthma Conclusions Our method identified dynamic functional asthma and healthy phenotypes, partly independent of atopy and inflammation but related to genetic markers on the 17q21 locus The method can be used for disease phenotyping and possibly endotyping It may identify participants with specific functional abnormalities, potentially needing a different therapeutic approach

Functional phenotypes determined by fluctuation-based clustering of lung function measurements in healthy and asthmatic cohort participants

Aims: To identify distinct asthma control clusters based on Control of Allergic Rhinitis and Asthma Test (CARAT) and to compare patients’ characteristics among these clusters. Methods: Adults and adolescents (≥13 years) with persistent asthma were recruited at 29 Portuguese hospital outpatient clinics, in the context of two observational studies of the INSPIRERS project. Demographic and clinical characteristics, adherence to inhaled medication, beliefs about inhaled medication, anxiety and depression, quality of life, and asthma control (CARAT, >24 good control) were collected. Hierarchical cluster analysis was performed using CARAT total score (CARAT -T). Results: 410 patients (68% adults), with a median (percentile 25–percentile 75) age of 28 (16 -46) years, were analysed. Three clusters were identified [mean CARAT -T (min -max)]: cluster 1 [27(24 -30)], cluster 2 [19(14 -23)] and cluster 3 [10(2 -13)]. Patients in cluster 1 (34%) were characterised by better asthma control, better quality of life, higher inhaler adherence and use of a single inhaler. Patients in clusters 2 (50%) and 3 (16%) had uncontrolled asthma, lower inhaler adherence, more symptoms of anxiety and depression and more than half had at least one exacerbation in the previous year. Furthermore, patients in cluster 3 were predominantly female, had more unscheduled medical visits and more anxiety symptoms, perceived a higher necessity of their prescribed inhalers but also higher levels of concern about taking these inhalers. There were no differences in age, body mass index, lung function, smoking status, hospital admissions or specialist physician follow -up time among the three clusters. Conclusion: An unsupervised method based on CARAT-T, identified 3 clusters of patients with distinct, clinically meaningful characteristics. The cluster with better asthma control had a cut -off similar to the established in the validation study of CARAT and an additional cut -off seems to distinguish more severe disease. Further research is necessary to validate the asthma control clusters identified.

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Serviço de Imunoalergologia, Centro Hospitalar Universitário do Algarve, Portimão

Papers

Identification of clusters of asthma control: A preliminary analysis of the Inspirers studies