Bronchiectasis: From targets to therapies

Figures & data

Table 1. Causes of bronchiectasis.

Post-infectious
Bacteria (Staphylococccus aureus, Bordetella pertussis, NTM, others)
Mycobacterium tuberculosis
Aspergillus sp.
Viruses (adenovirus, influenza, SARS-CoV-2, others)
Idiopathic (most often post-infectious)
Chronic obstructive lung diseases
Chronic obstructive pulmonary disease (COPD)
Asthma
Allergic bronchopulmonary aspergillosis
Inhalation, aspiration, or substance abuse
Foreign body aspiration
Gastro-esophageal reflux
Chlorine gas inhalation
Intoxication (heroin)
Collagen vascular disease
Rheumatoid arthritis
Scleroderma
Systemic lupus erythematosus
Sjögren’s syndrome
Relapsing polychondritis
Immunodeficiencies
Primary
Hypogammaglobulinemia (ex. common variable immunodeficiency)
Secondary
Chronic lymphocytic leukemia, multiple myeloma
Immunosuppression (ex. post-transplant)
Chemotherapy
B-cell targeted immunotherapies
HIV infection
Protein-losing enteropathies (ex. inflammatory bowel diseases, others)
Congenital
Primary ciliary dyskinesis	Mounier–Kuhn syndrome
Cystic fibrosis	Williams–Campbell syndrome
Genetic primary hypogammaglobulinemia	Marfan syndrome
Alpha1-antitrypsin deficiency	Ehlers-Danlos syndrome
Pulmonary sequestration
Other
Young’s syndrome
Yellow nail syndrome

Table 2. Potential targets for therapeutic intervention in bronchiectasis.

Target	Rationale	Potential interventions
Muco-ciliary clearance	Concentrated airway mucins (Muc5B, Muc5AC) inhibit phagocytosis, cationic peptide bactericidal activity, and suppress phagocytic oxidative burst. Primary ciliary dyskinesia and CF confirm the importance of muco-ciliary clearance to prevent bronchiectasis. CFTR activity is decreased in the airways of CF and COPD.	CFTR modulators in CF CFTR potentiator in bronchiectasis (QBW251: NCT04396366). Thiol-targeted mucolytics (ARINA-1, NCT05495243; P3001, PMID: 30212240) 7% hypertonic saline (EudraCT 2020-001026-62)
Host immune defense	Multiple host defense deficiencies with primary defects in antibody production are associated with bronchiectasis. Secondary immunodeficiencies include but are not limited to CVID, HIV, GVH disease, CLL, MM, and other malignancies.	IVIG, SCIG Treatment of underlying immunodeficiency CSL787 (inhaled IgG, NCT04643587)
Neutrophilic airway inflammation	HLE is a major predictor of poor outcomes in bronchiectasis. HLE increases airway wall compliance and mucus gland secretion, inhibits neutrophil efferocytosis and apoptosis, cleaves antibodies, complement and phagocyte ligand receptors needed for opsonin-dependent phagocytosis.	Azithromycin (PMID: 33609487) HLE inhibition. DPP-1 (cathepsin-C) inhibition (BI 1291583, NCT05238675; EudraCT 2021-003304-41) Brensocatib (PMID: 35976570, PMID: 32897034, NCT04594369, NCT05344508, EudraCT 2020-003688-25)
Eosinophilic airway inflammation	Eosinophils are important effector cells for type-2 immunity and are involved with airway remodeling, mucus plugging, and exacerbations in asthma. Asthma and bronchiectasis frequently overlap The significance of eosinophilic non-CF/non-asthmatic-bronchiectasis is unclear	Inhaled corticosteroids (PMID: 32398295) Type-2 targeting cytokines (e.g. with anti-IL-5 mepolizumab, PMID: 34098492)
Bacterial load	Pseudomonas aeruginosa suppression therapy decreases lung function loss and respiratory exacerbations in CF. Data less clear in non-CF bronchiectasis but suggestive of benefit. PROMIS program (inhaled colistin in non-CF bronchiectasis) has early positive results.	Inhaled tobramycin Colistimethate sodium nebulization solution (NCT03093974; NCT03460704) Phage cocktail against P. aeruginosa (AP-PA02, NCT05616221)
Prevention	CFTR dysfunction in smokers. Decreased lung exacerbations of bronchiectasis during COVID-19 lockdown.	Smoking cessation Vaccination (pneumococcal, HIB, influenza, SARS-CoV-2) Vaccine trials for prevention of respiratory viral infections. Antiviral drugs. Host TMPRSS-2 inhibitors (PMID: 35344983)

Abbreviations: CF: cystic fibrosis, CFTR: cystic fibrosis transmembrane conductance regulator, CLL: chronic lymphocytic leukemia, COPD: chronic obstructive pulmonary disease, CVID: common variable immune deficiency, EudraCT: European Union drug regulating authorities clinical trials, GVH: graft versus host, HIV: human immunodeficiency virus, HLE: human leukocyte elastase, IVIG: intravenous immunoglobulins, MM: multiple myeloma, SCIG: sub-cutaneous immunoglobulins, PMID: PubMed Identifier, NCT: clinical trial identifier used in the clinicaltrials.gov web site.