Rationale: Bronchiectasis is classically considered a neutrophilic disorder, but eosinophilic subtypes have recently been described. Objectives: To use multiple datasets available through the European Multicentre Bronchiectasis Audit and Research Collaboration to characterize eosinophilic bronchiectasis as a clinical entity focusing on the impact of eosinophils on bronchiectasis exacerbations. Methods: Patients were included from five countries to examine the relationships between blood eosinophil counts and clinical phenotypes after excluding coexisting asthma. 16S rRNA sequencing was used to examine relationships between eosinophil counts and the sputum microbiome. A post hoc analysis of the PROMIS (Inhaled Promixin in the Treatment of Non-Cystic Fibrosis Bronchiectasis) phase 2 trial was used to examine the impact of blood eosinophil counts on exacerbations in patients with Pseudomonas aeruginosa infection. Measurements and Main Results: A relationship between sputum and blood eosinophil counts was demonstrated in two cohorts. In analysis of 1,007 patients from five countries, 22.6% of patients had blood eosinophil counts of ⩾300 cells/μl. Counts of <100 cells/μl were associated with higher bronchiectasis severity and increased mortality. There was no clear relationship with exacerbations. Blood eosinophil counts of ⩾300 cells/μl 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 after treatment with antipseudomonal antibiotics. Compared with patients with blood eosinophil counts of <100 cells/μl (reference), elevated eosinophil counts of 100-299 cells/μl (hazard ratio, 2.38; 95% confidence interval, 1.33-4.25; P = 0.003) and ⩾300 cells/μl (hazard ratio, 3.99; 95% confidence interval, 2.20-7.85; P < 0.0001) were associated with shorter time to exacerbation. Conclusions: Eosinophilic bronchiectasis affects approximately 20% of patients. After accounting for infection status, raised blood eosinophil counts are associated with shortened time to exacerbation. 

/pdf/characterization-of-eosinophilic-bronchiectasis-a-european-206vx7dr.pdf

Characterization of Eosinophilic Bronchiectasis: A European Multicohort Study

Although bronchiectasis pathophysiology has been historically understood around the presence of airway neutrophilic inflammation, recent experiences are consistent with the identification of a type 2 inflammation (T2) high endotype in bronchiectasis. In order to evaluate prevalence and clinical characteristics of bronchiectasis patients with a T2-high endotype and explore their response to biologicals, two studies were carried out. In a cross-sectional study, bronchiectasis adults without asthma underwent clinical, radiological, and microbiological assessment, along with blood eosinophils and oral fractional exhaled nitric oxide (FeNO) evaluation, during stable state. Prevalence and characteristics of patients with a T2- high endotype (defined by the presence of either eosinophils blood count ≥300 cells·µL−1 or oral FeNO ≥ 25 dpp) were reported. A case series of severe asthmatic patients with concomitant bronchiectasis treated with either mepolizumab or benralizumab was evaluated, and patients’ clinical data pre- and post-treatment were analyzed up to 2 years of follow up. Among bronchiectasis patients without asthma enrolled in the cross-sectional study, a T2-high endotype was present in 31% of them. These patients exhibited a more severe disease, high dyspnea severity, low respiratory function, and high impact on quality of life. Among the five patients with severe eosinophilic asthma and concomitant bronchiectasis included in the series, treatment with either mepolizumab or benralizumab significantly reduced the exacerbation rate with an effect that persists for up to 2 years of follow up. If validated across different settings, our data suggest the need to design randomized controlled trials on biological treatments targeting the T2-high endotype in bronchiectasis patients.

T2-High Endotype and Response to Biological Treatments in Patients with Bronchiectasis.

Supplement to: Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. Elisabeth Bel;Sally Wenzel;Philip Thompson;Charlene Prazma;Oliver Keene;Steven Yancey;Hector Ortega;Ian Pavord; The New England Journal of Medicine

Supplement to: Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.

Rationale: Although inflammation and infection are key disease drivers in bronchiectasis, few studies have integrated host inflammatory and microbiome data to guide precision medicine. Objectives: To identify clusters among bronchiectasis patients based on inflammatory markers and assess the association between inflammatory endotypes, microbiome characteristics, and exacerbation risk. Methods: Stable bronchiectasis patients were enrolled at three European centers and cluster analysis was used to stratify the patients according to the levels of 33 sputum and serum inflammatory markers. Clusters were compared in terms of microbiome composition (16S rRNA sequencing) and exacerbation risk over 12 months follow-up. Measurements and Main Results: 199 patients were enrolled (109 [54.8%] female, median age 69 years). Four clusters of patients were defined according to their inflammatory profiles: cluster 1 (milder neutrophilic inflammation), cluster 2 (mixed-neutrophilic and type 2), cluster 3 (most severe neutrophilic), and cluster 4 (mixed-epithelial and type 2). Lower microbiome diversity was associated with more severe inflammatory clusters (P<0.001), and beta-diversity analysis demonstrated distinct microbiome profiles associated with each inflammatory cluster (P=0.001). Proteobacteria and Pseudomonas at phylum and genus levels, respectively, were more enriched in clusters 2 and 3 than in clusters 1 and 4. Furthermore, patients in clusters 2 (rate ratio [RR] 1.49, 95% CI 1.16–1.92) and 3 (RR 1.61, 95% CI 1.12–2.32) were at higher risk of exacerbation over 12 months follow-up compared to cluster 1 even after adjustment for prior exacerbation history. Conclusion: Bronchiectasis inflammatory endotypes are associated with distinct microbiome profiles and future exacerbation risk. 

Inflammatory Molecular Endotypes in Bronchiectasis: A European Multicenter Cohort Study.

Bronchiectasis and Eosinophils

Patients with clinically significant bronchiectasis featuring an eosinophilic inflammatory endotype who were treated with add-on mepolizumab or benralizumab showed a significant improvement of FEV1, symptom burden and quality of lifehttp://bit.ly/2AZvBLm

https://erj.ersjournals.com/content/erj/55/1/1901333.full.pdf

Anti-IL5 and anti-IL5Rα therapy for clinically significant bronchiectasis with eosinophilic endotype: a case series

Purpose Asthma is associated with a high prevalence of psychopathological disorders, especially depressive disorders or anxiety. In patients with uncontrolled severe asthma, monoclonal antibody (mAb)-therapy positively influenced control of mental disorders. Therefore, we evaluated the impact of antibody therapy on the burden of these mental diseases depending on responder status. Patients and Methods Data were collected retrospectively in patients with uncontrolled severe asthma (n = 82) prior to mAb-therapy (“baseline”) (omalizumab, dupilumab, benralizumab or mepolizumab). Symptoms of Major Depressive Disorder (MDD) or General Anxiety Disorder (GAD) were detected at baseline using the Hospital Anxiety and Depression Scale (HADS), as well as general sociodemographic data and lung function parameters. At 6-month (±3 month) follow-up, the burden of psychopathological symptoms under mAb-therapy was assessed using the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder Scale-2 (GAD-2). Response status was classified using the Biologics Asthma Response Score (BARS), assessing exacerbations, oral corticosteroid usage and asthma control test (ACT) score. Predictors for non-response to mAb-therapy were identified using linear regression analysis. Results Patients with severe asthma suffered from symptoms of MDD/GAD more often compared to the general population, with a higher prevalence among mAb therapy non-responders. mAb-responders exhibited a declining burden of MDD, better quality of life (QoL), less exacerbations, better lung function and better disease control compared to non-responders. A history of symptoms of depression was identified as a predictor for non-response to mAb-therapy. Conclusion Asthma symptoms and psychological problems are linked and more prevalent in our cohort of severe asthma patients than in the general population. Patients with signs of MDD/GAD before mAb-therapy show less mAb therapy response suggesting a negative impact of prior psychological problems on treatment response. In some patients, the score on MDD/GAD was caused by severe asthma – here symptoms decreased after effective treatment.

https://www.dovepress.com/getfile.php?fileID=89049

Relationship Between the Response to Antibody Therapy and Symptoms of Depression and Anxiety Disorders in Patients with Severe Asthma

Eradication of Pseudomonas aeruginosa within the baseline dataset of the German Bronchiectasis Registry PROGNOSIS

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Anti-IL5 and anti-IL5Rα therapy for clinically significant bronchiectasis with eosinophilic endotype: a case series

Relationship Between the Response to Antibody Therapy and Symptoms of Depression and Anxiety Disorders in Patients with Severe Asthma

Eradication of Pseudomonas aeruginosa within the baseline dataset of the German Bronchiectasis Registry PROGNOSIS