Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity

Abstract

Bronchiectasis is characterised by pathological dilation of the airways. More specifically, the radiographic demonstration of airway enlargement is the common feature of a heterogeneous set of conditions and clinical presentations. No approved therapies exist for the condition other than for bronchiectasis caused by cystic fibrosis. The heterogeneity of bronchiectasis is a major challenge in clinical practice and the main reason for difficulty in achieving endpoints in clinical trials. Recent observations of the past 2 years have improved the understanding of physicians regarding bronchiectasis, and have indicated that it might be more effective to classify patients in a different way. Patients could be categorised according to a heterogeneous group of endotypes (defined by a distinct functional or pathobiological mechanism) or by clinical phenotypes (defined by relevant and common features of the disease). In doing so, more specific therapies needed to effectively treat patients might finally be developed. Here, we describe some of the recent advances in endotyping, genetics, and disease heterogeneity of bronchiectasis including observations related to the microbiome.

Figure 1.. Model describing the pathogenesis of bronchiectasis.

A cycle of events that promote a persistent and progressive process over time. Impaired mucociliary clearance and retention of airways phlegm disrupt normal host defenses, renderings the airways vulnerable to infection, which can become persistent. This, in turn, incites an inflammatory response causing injury and abnormal remodeling of the airways leading to bronchiectasis.

Figure 2.. CFTR mutation classification.

Cystic fibrosis transmembrane conductance regulators (CFTR) mutation classification based on molecular defect. These molecular defects correspond to therapeutic approaches to restore the quantity of protein and/or its function resulting in genotype specific CFTR modulator drugs used alone (ivacaftor) or in combination (lumacaftor/ivacaftor, tezacaftor/ivacaftor). Adapted from

Figure 3.. Ciliary dyskinesia gene classifications.

Defects in cilia genes can be classified based on ultrastructural effects seen on cross sectional examination of cilia with electron microscopy. Note that some genes can be mutated without obvious structural abnormalities. Adapted from

Figure 4.. Potential endotypes for idiopathic bronchiectasis patients with pulmonary NTM infections.

Characterization with biomarker measurements of sweat chloride, nasal NO, ciliary beat frequency, and body morphometrics coupled with the presence of relevant genetic variants may allow therapeutic targeting based on predominant endotype. Examples would be the potential use of CFTR modulators in patients that have a CF-predominant endotype , sildenafil or other nitric oxide pathway agonists for cilia-predominant endotype , TGF-beta attenuators such as losartan for heritable connective tissue-predominant endotype , and immune modulators such as GMCSF for immune deficient predominant endotype