Bronchiectasis enters the inflammation era.

Abstract

Bronchiectasis (BE) is an increasing global problem affecting children and adults. Historically regarded as an orphan condition, there has been an increase in both clinical and translational research in recent years. Pathophysiology of BE is understood in terms of the vicious vortex which has three key components leading to airway structural damage: impaired mucociliary clearance, airway infection and inflammation.1 While airway clearance through physiotherapy and antibiotic treatment has been the cornerstone of BE treatment for decades, there is a lack of effective therapies targeting inflammation.1, 2 Neutrophils are the most abundant inflammatory cells identified in the airways of patients with BE.1 Neutrophilic inflammation is a double-edged sword, leading on one hand to the release of harmful proteases and tissue damage, and on the other hand, contributing to immune defence. Previous clinical trials aiming to reduce neutrophil recruitment to the airway have shown similar patterns of increased infections. Understanding the mechanisms of neutrophilic inflammation is the key to unlocking new therapeutic targets. We recently conducted a series of studies with international collaborators in Spain, Italy and Australia to better understand the nature of neutrophilic inflammation in BE.1 Utilizing proteomic analysis of sputum samples, we identified that severe disease in BE was characterized by an upregulation of neutrophil and neutrophil extracellular trap (NET)-associated proteins.1 We validated these findings in two large cohort studies and found that increased sputum NET complexes were associated with disease severity, reduced quality of life, severe exacerbations and mortality. Azithromycin treatment has been proven to reduce exacerbation frequency, including in patients with Pseudomonas aeruginosa infection which is intrinsically resistant to the antibiotic effect of macrolides. Analysis of two long-term studies of azithromycin, one in BE and the AMAZES trial in asthma, demonstrated that NETs could be reduced, and clinical outcomes improved with macrolide treatment.1 This provides a potential mechanism for the beneficial effects of macrolides, particularly in patients with neutrophilic disease. Our results suggest that NETs may contribute to symptoms and exacerbations in BE and NETs are likely to be the primary mechanism by which harmful neutrophil serine proteases such as elastase are released and damage the airway. We recently reported the results of a phase 2 study of a DPP1 inhibitor in BE patients with a history of exacerbations. A total of 256 patients with BE were randomized to either two doses (10 and 25 mg) of the DPP1 inhibitor brensocatib or placebo and followed up for 6 months.2 DPP1 inhibition prevents the activation of the neutrophil proteases elastase, cathepsin-G and proteinase-3 in the bone marrow. Brensocatib treatment at both doses prolonged the time to first exacerbation and was associated with marked reductions in sputum neutrophil elastase. There were small numerical increases in skin and dental adverse effects in the phase 2 trial but no increase in infection risk. While the encouraging results need to be confirmed in a larger phase 3 trial, these data suggest the potential to directly target neutrophilic inflammation in patients with BE.2 BE is a heterogeneous disease and although neutrophilic inflammation and infection represent the most common ‘endotype’, clinical experience and clinical trial results suggest that there are other important contributors to disease burden and exacerbation.3, 4 Eosinophils are well-established drivers of exacerbation in asthma and chronic obstructive pulmonary disease, but until recently their role in BE was not established. Shoemark et al. recently reported the results of a pan-European cohort of 1007 patients with BE. This study showed that based on sputum eosinophil counts >3%, the gold standard for defining eosinophilic inflammation in sputum, approximately 20% of BE patients have eosinophilic inflammation after the exclusion of patients with asthma and allergic bronchopulmonary aspergillosis. Eosinophil counts in blood >300 cells/μl were shown to be a valid surrogate marker of sputum counts. In a sub-study of 144 patients, eosinophilic inflammation in blood was associated with increased risk of exacerbation.3 Oriano et al. extended these observations by also incorporating measurement of FeNO showing that a Th2-high endotype of BE was present in 31% of patients when considering a high eosinophil count (>300 cells/μl) and a raised FeNO ≥25 dpp. Patients with T2-high inflammation had more severe disease and worse symptoms.4 These studies demonstrate that BE is not exclusively a neutrophilic disease. Eosinophilic inflammation may contribute to a subset of BE exacerbations and biomarkers may be useful to target anti-eosinophil strategies such as inhaled corticosteroids or anti-IL5 therapies in future. Observational studies and post hoc analyses of randomized trials already suggest that eosinophil counts in blood may predict treatment responses in BE, although these results need to be confirmed in prospective trials.5 BE is therefore entering a new era where patients can be potentially classified into inflammatory endotypes based on the presence of neutrophilic or eosinophilic (or mixed) profiles which may require different treatments. Ongoing phase 3 trials of both anti-neutrophil (NCT04594369) and anti-eosinophil (NCT05006573) anti-inflammatory strategies represent important opportunities to transform the management of BE. Infection remains a crucial component of the vicious vortex, and targeting inflammation cannot ignore the important contribution of the airway microbiome. While much research has focused on the roles of conventional pathogens such as P. aeruginosa, which are consistently associated with poor clinical outcomes, recent research using next-generation sequencing has given us a more nuanced view of the role of bacteria in BE.6, 7 The concept of ‘good bacteria’ in the microbiome is well accepted in the gut but poorly defined in the airways. Commensals such as Rothia may have a beneficial effect on inflammation, as demonstrated in a recent study by Rigauts et al. Using murine models, Rothia mucilaginosa was shown to have an inhibitory effect on pathogen and LPS-induced proinflammatory responses through inhibiting nuclear factor kappa B (NF-kB) pathway activation. In sputum samples obtained from BE patients, Rothia spp. were negatively correlated with pro-inflammatory mediators, demonstrating that the presence of this organism in the lower airways may reduce inflammation.6 These studies add to evidence that the interactions between bacteria are important in determining patient outcomes7 and demonstrate that modulation of the microbiome may be a powerful tool in reducing inflammation. How to modulate the microbiome remains a challenging question. Our studies using proteomics found that antibiotic treatment in patients with dominance of Gram-negative organisms such as Pseudomonas and Haemophilus reduces neutrophilic inflammation and upregulates antiprotease defence.1 Whether the microbiome can be modified using non-antibiotic approaches such as immune modulators or probiotics requires investigation. BE therapy is entering a new era where immune-modulating therapy has a key role alongside airway clearance and antibiotics. Classifying patients into endotypes, based on neutrophilic, eosinophilic or mixed inflammatory profiles, offers a range of treatment targets under a personalized medicine approach. Targeting inflammation directly, through treatments such as DPP1-inhibition, and indirectly through modulation of the microbiome may both lead to improvements in patient outcomes in the future. Holly R. Keir and James D. Chalmers are funded by Asthma and Lung UK. Holly R. Keir declares no conflicts of interests. James D. Chalmers reports research grants and consultancy from Astrazeneca, Boehringer Ingelheim, Chiesi, Gilead Sciences, Glaxosmithkline, Grifols, Insmed, Novartis, Pfizer and Zambon.