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Rationale: Bronchiectasis is classically considered a neutrophilic disorder but eosinophilic subtypes have recently been described.Objectives: To use multiple datasets available through the EMBARC consortium to characterise eosinophilic bronchiectasis as a clinical entity focussing on the impact of eosinophils on bronchiectasis exacerbations.Methods: Patients were included from 5 countries to examine the relationships between blood eosinophil counts and clinical phenotypes after excluded co-existing asthma. 16S rRNA sequencing was used to examine relationships between eosinophil counts and the sputum microbiome. A posthoc analysis of the PROMIS phase 2 trial was used to examine the impact of blood eosinophil counts on exacerbations in patients with P.aeruginosa infection. Measurements and MainResults: A relationship between sputum and blood eosinophil counts was demonstrated in 2 cohorts. In analysis of 1007 patients from 5 countries, 22.6% of patients had blood eosinophil counts >300cells/ul. Counts<100cells/ul were associated with higher bronchiectasis severity and increased mortality. There was no clear relationship with exacerbations. Blood eosinophil counts >300cells/ul were associated with both Streptococcus and Pseudomonas dominated microbiome profiles. To investigate the relationship of eosinophil counts with exacerbations after controlling for the confounding effects of infection, 144 patients were studied in a clinical trial following treatment with antipseudomonal antibiotics. Compared to patients with blood eosinophil counts<100cells(reference), elevated eosinophil counts 100-300cells/ul p=0.003) and >300cells/ul p<0.0001) were associated with shorter time to exacerbation. Conclusion:Eosinophilic bronchiectasis affects approximately 20% of patients. After accounting for infection status, raised blood eosinophil counts are associated with shortened time to exacerbation.

IntroductionNeutrophil elastase activity in sputum can identify patients at high risk of airway infection and exacerbations in bronchiectasis. Application of this biomarker in clinical practice is limited, because no point-of-care test is available. We tested whether a novel semi-quantitative lateral flow device (neutrophil elastase airway test stick – NEATstik®) can stratify bronchiectasis patients according to severity, airway infection and exacerbation risk.MethodsSputum samples from 124 patients with stable bronchiectasis enrolled in the UK and Spain were tested using the NEATstik®, which scores neutrophil elastase concentration from 0 (<8 µg·mL−1 elastase activity) to 10 (maximum detectable neutrophil elastase activity). High neutrophil elastase activity was regarded as a NEATstik® grade >6. Severity of disease, airway infection from sputum culture and exacerbations over the 12 months were recorded. An independent validation was conducted in 50 patients from Milan, Italy.Measurements and main resultsPatients had a median age of 69 years and forced expiratory volume in 1 s (FEV1) 69%. High neutrophil elastase activity was associated with worse bronchiectasis severity using the bronchiectasis severity index (p=0.0007) and FEV1 (p=0.02). A high NEATstik® grade was associated with a significant increase in exacerbation frequency, incident rate ratio 2.75 (95% CI 1.63–4.64, p<0.001). The median time to next exacerbation for patients with a NEATstik® grade >6 was 103 days compared to 278 days. The hazard ratio was 2.59 (95% CI 1.71–3.94, p<0.001). Results were confirmed in the independent validation cohort.ConclusionsA novel lateral flow device provides assessment of neutrophil elastase activity from sputum in minutes and identifies patients at increasing risk of airway infection and future exacerbations.

At a Glance CommentaryScientific knowledge on the subject: Chronic obstructive pulmonary disease (COPD) and bronchiectasis are two diseases with overlapping clinical presentation. Co-diagnosis of both diseases commonly occurs in some patients (termed as the 'COPD-bronchiectasis association') but the mechanisms, risk factors and potential management options for patients with the 'COPD-bronchiectasis association' are largely unknown. We hypothesized that the 'COPD-bronchiectasis association' syndrome would have an underlying pathophysiology different from COPD but similar to bronchiectasis, and the resulting molecular and microbial features would produce biologically informed patient classification. What this study adds to the field:We demonstrate for the first time that patients with COPD and the 'COPD-bronchiectasis association' presented different profiles in their lung microbiota and host responses, and that the underlying pathophysiology of the 'COPDbronchiectasis association' is closer to that of bronchiectasis. These results were validated in an independent cohort showing that neutrophilic inflammation, increased abundance of pathogenic proteobacteria and dysregulation of mucins are key processes associated with bronchiectasis and the COPD-bronchiectasis association. We propose here a biologically informed patient classification for airways disease patients according to their clinical, sputum microbiome and protein profiles.

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