Treatable traits in bronchiectasis

Abstract

]. The diagnostic label "bronchiectasis" describes the existence of localised and permanent airway dilation, but when used to describe a disease it includes a heterogeneous group of disorders that differ significantly in terms of aetiological, clinical, radiological, functional and microbial features [1]. Using cluster analysis, some previous studies have attempted to identify distinct "clinical phenotypes" in patients with bronchiectasis [2-4] (defined as "a single or combination of disease attributes that describe differences between patients that are related to clinically meaningful outcomes" [5]). By and large, however, these studies did not consider the underlying biology or response to therapy (i.e. the underlying endotype(s) [6]). Potential endotypes in bronchiectasis include immunodeficiency, ciliary dyskinesia, infection (with typical bacteria and non-tuberculous mycobacteria (NTM)), hypersensitivity to fungi and autoimmunity. Importantly, all of them can potentially become therapeutic targets [7]. The main treatment goals in bronchiectasis are to reduce symptoms, prevent exacerbations and lung function decline and, ultimately, improve survival. Unfortunately, most currently available therapeutic options have shown only a modest impact on disease outcomes in randomised clinical trials [8, 9]. For instance, inhaled antibiotic treatments have, so far, produced only modest benefits in terms of reduced exacerbations or improved quality of life, suggesting that endotypes other than airway "infection" are likely to play a relevant pathogenic role [10-12]. Likewise, co-existing airways diseases are common in patients with bronchiectasis and, in fact, up to 50% of these patients have a diagnosis of co-existing asthma or chronic obstructive pulmonary disease (COPD) [13, 14]. All in all, the complexity of bronchiectasis is poorly adapted to the "one size fits all" approach of current clinical guidelines. The coexistence in the same patient of different endotypes, clinical phenotypes and exposures requires a more precise approach to both assessment and therapy. The concept of "treatable traits" was originally proposed in 2016 by AGUSTI et al. [15] in the European Respiratory Journal as a way toward precision medicine of airway diseases. These authors argued that the current airways disease diagnostic labels are imprecise, often overlap and lead to empirical therapy. They proposed that a biomarker-directed approach, based on the recognition of clinical phenotype and endotypes, can help to personalised treatment options which, hopefully, may result in better clinical outcomes. In the original manuscript on treatable traits, bronchiectasis was considered as a potential trait in patients with a diagnostic label of asthma or COPD. Here, we leverage from the treatable traits concept [15] and suggest that patients with bronchiectasis, with or without co-existing COPD and asthma, represent a heterogeneous group of patients who also present multiple treatable traits, many of which go

Long-term macrolide antibiotics for the treatment of bronchiectasis in adults: an individual participant data meta-analysis

“…3,4 Bronchiectasis is characterised by a "vicious vortex" of bacterial infection, airway inflammation and impaired mucociliary clearance which each interact to promote lung damage. 5,6 There are few evidence based treatments for bronchiectasis as reflected in the recent European Respiratory Society bronchiectasis management guidelines which were unable to recommend any pharmacotherapy with a high quality of evidence. 7 Macrolide antibiotics are among the most widely used chronic treatments to prevent exacerbations in bronchiectasis.…”

Bronchiectasis and cough: An old relationship in need of renewed attention

“…More recent evidence corroborates this finding, highlighting objectively monitored cough frequency as an important predictor of sputum production and exacerbations (though not lung function) in bronchiectasis [21]. Indeed, such is the importance of cough, specifically cough hypersensitivity, that it has been advanced as a 'treatable trait' of bronchiectasis and proposed as a potential target of individualised therapies to alleviate cough in particularly symptomatic individuals [3,10]. Therapies such as use of antitussives, inhaled corticosteroids (ICS) or chest physiotherapy may therefore alleviate symptoms in individuals with problematic cough if appropriately targeted [10,22].…”

“…In addition, only modest benefit from directed pathogen-drug treatment is observed, which appears in contrast to that expected from Cole's vicious cycle hypothesis. This likely reflects the complexity of this disease of which infection is only one of many other pulmonary, extra-pulmonary, aetiological and environmental factors influencing disease [3,9,10]. Newer emerging models such as the 'vicious vortex' proposed by Flume and colleagues perhaps offers a more complete picture of disease pathogenesis [9].…”

“…Indeed, such is the importance of cough, specifically cough hypersensitivity, that it has been advanced as a 'treatable trait' of bronchiectasis and proposed as a potential target of individualised therapies to alleviate cough in particularly symptomatic individuals [3,10]. Therapies such as use of antitussives, inhaled corticosteroids (ICS) or chest physiotherapy may therefore alleviate symptoms in individuals with problematic cough if appropriately targeted [10,22]. While bronchiectasis mandates multifaceted management with consideration of heterogeneous clinical features, co-morbidities, microbiology, inflammation and therapeutic responses, cough remains an important common phenotypic trait but also a key symptom in the definition of a bronchiectasis exacerbationa major endpoint applied in almost all clinical trials and an important prognostic indicator of disease progression [23,24].…”

“…Effects were most pronounced in specific patient subgroupssuch as those colonised by basidiomycetous fungireinforcing the importance of microbiology and the targeted, personalised approach likely required. The potential application of antifungal therapeutics in bronchiectasis should however be targeted to specific disease subtypes, such as those driven by fungal allergy and, here, the identity of the inciting fungal species may be critically important [4,5,10,35,56].…”