Shifting paradigm in bronchiectasis: Q&A on neutrophil extracellular traps and targeting inflammation

Research on the importance of neutrophil extracellular traps (NETs) in bronchiectasis is gaining ground, with a recent Lancet paper finding NETs to be a key marker of disease severity and treatment.

the limbic caught up with senior author Professor James Chalmers, Consultant Respiratory Physician at the University of Dundee and lead author Holly Keir, who won the British Thoracic Society Early Career Investigator Award at the 2021 BTS Winter Meeting, to find out more.

Why is better understanding of NET formation potentially so important in bronchiectasis?

JC: There are no licensed treatments for bronchiectasis and no proven anti-inflammatory drugs. We urgently need to identify new non-antibiotic treatments. To the best of our knowledge, this is the first study that identified NET formation in bronchiectasis as the dominant inflammatory pattern in severe bronchiectasis, highlighting a potential therapeutic target.

HK: Targeting NETosis may theoretically reduce a broad range of neutrophil and downstream inflammatory mediators without compromising neutrophil recruitment and function. Trials of therapies that can target this mechanism are already underway.

Your paper in The Lancet helps to bridge that gap between laboratory science and what is happening with patients. Can you quickly explain what this study showed that we didn’t know or weren’t completely clear about before?

HK: Clinicians have been very focused on structural lung damage and infection in bronchiectasis, but inflammation has been largely ignored as it is difficult to study.

This research identifies, for the first time, NET formation in the lungs of patients with bronchiectasis and demonstrates that the presence of NETs is associated with disease severity, severe exacerbations and mortality. Additionally, NET levels can be reduced through macrolide and antibiotic therapies, leading to improved outcomes for patients.

JC: It is a laboratory study with important implications for patients – firstly, outcomes are linked to inflammation which means treatment needs to be focused on reducing inflammation, a concept that transformed the field of asthma for example, but which is not currently considered in bronchiectasis.

Secondly, we offer a potential answer to why antibiotics and macrolides improve symptoms in bronchiectasis by showing that they reduce NETs. Knowing this will help us target these treatments better as well as supporting the development of new treatments.

What do we still need more information/evidence on regarding the formation of NETs in bronchiectasis? What do we still not fully understand?

HK: We don’t yet fully know why neutrophils from patients with bronchiectasis form NETs. Understanding this would make it easier to develop new treatments. It is likely that infection is a key driver as in this study we demonstrate an association between NET formation and proteobacteria, Pseudomonas and Haemophilus.

We show that reducing bacterial load correlated with a reduction in NET levels, suggesting that proteobacteria may drive NET formation which is consistent with previous literature. This is, however, only likely to be part of the story.

What are the implications for using these markers? Might they be used to diagnose and direct treatment?

JC: This study identifies a subset of patients with P. aeruginosa infection and high NET levels, who respond positively to macrolide treatment through anti-inflammatory effects. This, along with other data, suggests that for patients with P. aeruginosa infection and frequent exacerbations macrolides should be considered for macrolide treatment.

Looking to the future, there are already indirect measures of NETs such as point of care testing for neutrophil elastase that are in development, so although we can’t yet measure NETs and inflammation directly in the clinic, this may be possible in the near future.

In the longer term what are the potential treatment implications for patients with bronchiectasis?

JC: It is a really exciting time for bronchiectasis. A recent randomised study of DPP1 inhibition in bronchiectasis showed for the first time the benefit of directly targeting neutrophilic inflammation, opening up a completely new method of treatment for the disease. In this study, time to first exacerbation was significantly prolonged using an anti-inflammatory treatment compared to placebo.

HK: Our study demonstrates the mechanistic basis for this therapy and suggests alternative immunomodulatory treatments that target NETs could also be effective. This needs to be demonstrated in future trials, but given the orphan nature of bronchiectasis it is very encouraging that we now understand much more about how inflammation influences the severity of disease and how treatments are working to improve symptoms and reduce exacerbations.

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