Bronchiectasis: From targets to therapies

Abstract

Bronchiectasis is a chronic obstructive airway disease characterized by abnormal bronchial dilatation and the accumulation of muco-purulent endoluminal secretions. Progressive lung function deterioration, frequent bouts of respiratory infection and daily productive cough negatively impact the lives of affected individuals. Multiple causal factors can initiate bronchiectasis; however, defects in host defenses represent a cardinal feature. The first line of airway defense against inhaled pathogens is mucociliary clearance. Systemic host defense defects, particularly those affecting opsonophagocytosis and killing of bacteria are equally essential to prevent bronchiectasis. Substantial evidence suggests that unopposed neutrophil protease activity in the airway lumen leads to the loss of bronchial elasticity and excessive accumulation of mucus. The focus of this review is on the advances in our understanding of pathogenic mechanisms that are bringing new targeted therapies for individuals suffering from the clinical manifestations of bronchiectasis.

RÉSUMÉ

La bronchectasie est une maladie obstructive chronique des voies respiratoires caractérisée par une dilatation anormale des bronches et l’accumulation de sécrétions endoluminales muco-purulentes. La détérioration progressive de la fonction pulmonaire, les épisodes fréquents d’infection respiratoire et la toux productive quotidienne ont des répercussions négatives sur la vie des personnes touchées. De multiples facteurs causaux peuvent êre à l’origine de la bronchectasie, mais les déficiences dans les mécanismes de défense de l’hôte représentent une caractéristique essentielle. La première ligne de défense des voies respiratoires contre les agents pathogènes inhalés est la clairance mucociliaire. Les déficiences systémiques des mécanismes de défense de l’hôte, en particulier celles qui affectent l’opsonophagocytose et la destruction des bactéries, sont tout aussi essentielles pour prévenir la bronchectasie. Des preuves considérables indiquent que l’activité protéasique des neutrophiles sans opposition dans la lumière des voies respiratoires entraîne une perte d’élasticité bronchique et une accumulation excessive de mucus. Cette revue se concentre sur les progrès dans notre compréhension des mécanismes pathogènes qui apportent de nouvelles thérapies ciblées pour les personnes souffrant des manifestations cliniques de la bronchectasie.

Keywords:

• Bronchiectasis
• cystic fibrosis
• immunosuppression
• infection
• inflammation

Introduction

Bronchiectasis is a chronic lung disease characterized by sustained, abnormally enlarged bronchi containing excessive stagnant, concentrated mucus that fuels an infamous “vicious circle” of infection, neutrophil elastase-dominated inflammation, airflow obstruction and tissue destruction.^1,2 The causes of bronchiectasis are numerous, heterogeneous and vary considerably according to the age and geographic region of affected individuals (Table 1).³ Characterization of genetic, microbiological and environmental features in individuals is fundamental to the management of bronchiectasis. Unfortunately for most individuals, a treatable cause of bronchiectasis cannot be identified. However, a better understanding of treatable traits that define endotypes as suggested by Flume et al.,⁴ is likely to improve patient care and accelerate the discovery of effective new therapies that slow or stop disease progression.

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

Several morphological types of bronchiectasis are associated with bronchomalacia (airway wall destruction), including cylindrical, varicose and cystic or saccular bronchiectasis.⁵ A distinct category of bronchiectasis is traction bronchiectasis in which bronchomalacia is not prominent, but dilatation is generated by an increase in the tension of peri-bronchial fibers acting on the airways. Clinical manifestations of traction bronchiectasis correlate with the severity of the underlying interstitial lung disease.⁶ The focus of the current review is on bronchiectasis with bronchomalacia, not traction bronchiectasis.

The prevalence of bronchiectasis is highest in women and in the elderly. Etiologies vary according to sex, age and geography. Causes of bronchiectasis have changed due to improved public health policies and patient care. Data from the European bronchiectasis EMBARC registry suggests that in Europe bronchiectasis following infections with tuberculosis, non-tuberculous mycobacteria (NTM), childhood Bordetella pertussis and other viruses have declined while COPD, asthma, connective tissue disease and immunodeficiency are more prevalent causes of bronchiectasis.⁷ Causes of bronchiectasis vary greatly between countries, with idiopathic and post-infectious accounting for between 40% and 70% of cases. In most areas of the world infections predisposing to bronchiectasis remain prominent.³ Documentation reporting the causes of bronchiectasis in many parts of the world remains sparse or absent.

The airway obstruction associated with bronchiectasis largely results from a loss of tissue elasticity and the accumulation of viscous secretions. The increase in airway compliance and mucus are both closely linked to the unabated presence of neutrophil proteases—especially human leukocyte elastase (HLE).^8,9

HLE present in neutrophil granules is essential for normal host defense against gram negative bacteria.¹⁰ A potential pitfall of targeting cellular HLE could be an increase in susceptibility to gram negative sepsis.¹¹ However, extracellular HLE represents an attractive therapeutic target.

The sustained presence of free, unopposed HLE in the extracellular compartment of the bronchial lumen is associated with worse infection, increased exacerbations and airway destruction in both cystic fibrosis (CF) and non-CF bronchiectasis.^12,13 Several proteins involved in airway structural integrity and host defenses are cleaved by HLE (reviewed by Voynow and Shinbashi).¹⁴ Proteases can cleave connective tissues thus increasing airway compliance.¹⁵ Furthermore, active extracellular HLE degrades several opsonins including immunoglobulin IgG, SP-A, SP-D, the complement protein fragment C3bi and the complement receptor CR1, creating an opsonin-receptor mismatch that suppresses phagocytosis and killing of bacterial pathogens.^16,17 The HLE-mediated phagocytosis and killing defect in bronchiectasis is reversed by in vivo inhibition of HLE using aerosolized alpha-1 antitrypsin.¹⁸ HLE also increases mRNA transcripts of the secreted airway mucin gene MUC5AC and induces airway mucus hypersecretion, a cardinal feature of bronchiectasis.^19,20 Other pro-inflammatory effects of HLE are the increased synthesis of the neutrophil chemoattractant IL-8 and cleavage of the macrophage phosphatidylserine receptor thus inhibiting macrophage clearance of apoptotic neutrophils (efferocytosis), which is essential for resolution of inflammation.^21,22 HLE also proteolyzes the key airway anti-bacterial host defense proteins transferrin, lactoferrin and midkine.¹⁴ Finally, HLE can cleave host airway antiproteases, alpha-1 antitrypsin and secretory leukoprotease inhibitor (SLPI).²³

Therapeutic attempts to directly inhibit HLE with alpha1 antitrypsin and other antiproteases have thus far been disappointing.¹⁴ The failure to translate HLE inhibition into an approved therapy for bronchiectasis largely reflects the difficulty of conducting definitive specific interventions in such a heterogeneous and complex disease, indicating that targeted treatments should be trialed in subgroups of patients where there may be a stronger rationale for targeting one of the pathogenic pathways leading to bronchiectasis morbidity. It may also suggest that if we are to improve the lives of people living with bronchiectasis, we need to focus on more than a single target.

Our understanding of the pathogenesis of bronchiectasis has greatly evolved in recent years. The remarkable improvements observed in individuals with CF who have benefited from the advent of highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy has sharpened our focus on mucociliary clearance as one of the major airway host defenses against chronic bacterial infection and tissue destruction.^24,25 Defective CFTR function is not limited to CF and is observed in healthy smokers and individuals with chronic obstructive pulmonary disease (COPD).^26,27 CFTR dysfunction also is induced by both host and pathogen-derived toxic products.^28,29 However, translating therapies that have proven helpful in CF to non-CF bronchiectasis is not simple. DNase I (dornase alpha) therapy improves lung function and decreases respiratory exacerbations in CF but has no beneficial effect in non-CF bronchiectasis, and may even cause harm.³⁰ Similarly, inhaled tobramycin markedly increases lung function in CF³¹ but has a more modest effect on lung function in non-CF bronchiectasis.³² The reasons for the differences in clinical responses between CF and non-CF bronchiectasis are poorly understood and may relate to CFTR-specific mechanisms, the severity of the CF airway mucus clearance defect or both. Regardless, knowledge obtained from studies of CF help inform us about the pathogenesis of bronchiectasis and potential therapeutic targets.

Therapeutic targets

Major targets for the development of new therapies in non-CF bronchiectasis are listed in Table 2. Some of the mechanisms associated with each of these targets have been extensively studied in both CF and non-CF bronchiectasis. The therapeutic interventions addressing each target have been the object of informative clinical trials in CF and several of these novel approaches are being studied in non-CF bronchiectasis.

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.

Muco-ciliary clearance

Formal airway clearance techniques (ACT) remain the cornerstone of therapy in bronchiectasis. Clinical trials of ACT present challenges in study design, patient recruitment, placebo control, blinding and length of study. However, a randomized placebo-controlled study over 1 year of the ACT known as ETGOL (slow expiration with the glottis opened in the lateral posture) in bronchiectasis suggests that there are numerous potential benefits of ACT.³³ These included improvements in the number of respiratory exacerbations, quality of life (St. George’s Respiratory Questionnaire) and decreased cough (Leicester Cough Questionnaire).

Airway mucus is predominantly comprised of the secreted airway mucins Muc5B, Muc5AC and small amounts of Muc2. Airway secreted mucins play 2 major host defense roles. First mucins, particularly Muc5B, are key to the trapping and clearing of inhaled pathogens and harmful particles through the mucociliary escalator.³⁴ Second, the anionic charge of airway mucins provides airway cells with an effective barrier protecting against oxidants and proteases.^35–37 These 2 roles of mucins are in opposition of one another since adequate airway clearance is associated with more fluid mucus whereas effective barrier protection requires thicker, viscous mucus. The successful switch back and forth from fluid to viscous mucus is a dynamic process dictated by numerous airway epithelial chloride and sodium channels of which CFTR plays a leading role. CFTR responds to environmental queues such as the chronic oxidative stress of repeated cigarette smoke exposure that decreases CFTR function and increases the protective mucus barrier. However, sustained accumulation of concentrated mucins in the airways as observed in certain CFTR deficiency states (CF, COPD), non-CF bronchiectasis and ciliary dyskinesia can also protect inhaled pathogens against host defenses and favor the proliferation of airway bacteria.^38–41 Recent data also suggest that increased mucin concentration and viscoelastic properties of spontaneously produced sputum predict sputum eosinophilia.⁴² These observations point to the importance of several potential interventions aimed at restoring healthy mucus transport in non-CF bronchiectasis such as smoking cessation, CFTR modulators and effective mucolytic agents to reduce mucus viscosity and improve mucociliary clearance.^43,44

The advent of highly effective CFTR modulator therapy (HEMT) in CF renders the clinical course of CF more like that of non-CF bronchiectasis and raises the question of whether HEMT-treated CF patients should be included in future bronchiectasis clinical trials. The answer is probably no. First, CFTR deficiency affects systemic immune responses which may not be fully normalized by HEMT. Second, many CF individuals have persistent severe pancreatic insufficiency, diabetes and liver abnormalities that can impact their ability to respond to infectious respiratory exacerbations, making them clearly distinct from those with non-CF bronchiectasis. Finally, the acquisition of unusual pathogens such as Burkholderia cepacia at an early age in CF is a distinguishing feature that can make comparisons with non-CF bronchiectasis imperfect.

Host immune defects

Immune deficiencies associated with reduced amounts of IgG, IgA and/or IgM immunoglobulins are clearly linked to an increased risk of developing bronchiectasis.⁴⁵ An increase in serum IgE may point to specific entities, particularly allergic bronchopulmonary aspergillosis or an immune dysregulation causing a hypereosinophilic syndrome. Both primary and secondary humoral immune deficiencies are significant risk factors for bronchiectasis, and serum immunoglobins should be assessed early after a diagnosis of bronchiectasis of unknown cause. Therapeutic interventions to compensate for immune deficiencies have shown significant benefit and novel Ig-replacement therapies continue to be explored.⁴⁶

Neutrophilic inflammation

The neutrophil serine proteases (NSPs) HLE, cathepsin G and proteinase III are activated through cathepsin C-dependent (CatC, also known as dipeptidyl peptidase 1, DPP-1) cleavage of an amino terminal dipeptide during the promyelocyte phase of neutrophil maturation.⁴⁷ Inhibitors of CatC block NSP activation. The CatC inhibitor AZD7986 (brensocatib) has shown a favorable early safety and tolerability profile in healthy humans.⁴⁸ Furthermore, a phase 2 clinical trial demonstrated that brensocatib prolongs the time to first exacerbation in non-CF bronchiectasis.⁴⁹ However, a potential pitfall of CatC inhibition is a decrease in host defense as reported in studies of olfactomedin-4. Olfactomedin-4 (OLFM4) is a matrix glycoprotein of neutrophil-specific granules which interacts with CatC and decreases the maturation of NSPs.⁵⁰ OLFM4 is present in 20–30% of circulating neutrophils from healthy individuals, and is more highly expressed during sepsis, acute respiratory distress syndrome and shock.⁵¹ Neutrophils from OLFM4^-/- mice have an increased killing capacity against Staphylococcus aureus and E. coli. In contrast, individuals with an elevated percentage of OLFM4 positive neutrophils (≥37.6%) had a higher 60-day mortality than those with a lower (<37.6%) percentage of OLFM4-positive neutrophils (60-day mortality: 56% in the high group, vs 18% in the low group, p < 0.001, n = 120).⁵² A possible interpretation of these results is that OLFM4 inhibits CatC-dependent activation of key NSPs critical to innate immune responses, thus increasing the risk of mortality during sepsis.

HLE-rich neutrophil extracellular traps (NET) have also been associated with non-CF bronchiectasis and are decreased with chronic macrolide therapy (discussed in a subsequent section) in the subgroup of patients with elevated markers of NETosis.⁵³ Finally, HLE inhibitors continue to garner interest but have yet to demonstrate sustained benefit in clinically meaningful outcomes.⁵⁴

Bacterial load

Individuals with bronchiectasis and chronic Pseudomonas aeruginosa (PA) infection of their airways are at a much higher risk of respiratory exacerbations, an accelerated rate of decline of lung function and increased hospitalizations.⁵⁵ Chronic PA suppressive therapy is recognized as a desirable objective in the treatment of bronchiectasis. Attempts to eradicate the first appearance of PA in sputum may also be of benefit.^56,57 Strategies to achieve these goals include inhaled antibiotics including tobramycin and colistimethate sodium. Inhaled tobramycin in bronchiectasis decreased the PA airway burden and, in some studies, reduced the number of exacerbations and hospital admissions (reviewed in Elborn et al.³²) The soon-to-be announced PROMIS trials (NCT03093974, NCT03460704) aim at assessing the use of a colistimethate sodium nebulization solution in non-CF bronchiectasis. Early positive clinical outcomes have been reported although definitive results of the 2 trials are yet to be published.⁵⁸ Preclinical studies of a phage anti-PA cocktail have led to the initiation of a clinical trial of this novel approach to suppress airway PA.⁵⁹

Macrolide therapy, particularly oral azithromycin, has been extensively studied in non-CF bronchiectasis as is discussed in a recent Cochrane review.⁶⁰ The review suggests that chronic azithromycin use in non-CF bronchiectasis is generally safe, reduces the number of respiratory exacerbations and improves quality of life while having limited or no effect on the number of hospitalizations. Several mechanisms by which chronic macrolide therapy may provide benefit have been proposed, including a decrease in the density of sensitive bacteria, a decrease in biofilm formation, and anti-inflammatory effects related to NETosis, but a single clear mechanism has not been identified. Potential adverse effects of macrolide therapy include cardiac (prolonged QT interval, arrythmias), otic (deafness and tinnitus) and microbiological (increased in pathogen, particularly NTM, antibiotic resistance) events.

Prevention of respiratory viral infections

During the COVID-19 pandemic one of the striking observations was that individuals with non-CF and CF bronchiectasis had a marked reduction in the number of respiratory exacerbations when compared to the period prior to the pandemic.⁶¹ Social distancing, immunization, wearing masks and rapid detection of respiratory viral infections likely contributed to the reduction in exacerbations. These observations should encourage us to explore and implement prevention of respiratory viral infections as a priority in the care of people with bronchiectasis. Host airway protease inhibition in SARS-CoV-2 and possibly influenza have shown promise in pre-clinical work.⁶²

Perspectives

In the past 3 years we have witnessed evidence that prevention of respiratory virus transmission is associated with a reduced number of infectious exacerbations in individuals with bronchiectasis. Further benefits likely include a decrease in post-viral airway damage and worsening of bronchiectasis. These observations reinforce the importance of an integrated approach to the prevention of respiratory viral transmission in our society. The recently observed dramatic improvements in lung function and quality of life in CF has also sharpened our focus on the importance of effective mucociliary clearance.

Clinical trials of CFTR modulator therapy, novel mucolytic drugs and airway clearance techniques represent important ongoing areas of investigation in non-CF bronchiectasis. New approaches to improve host immune deficiencies and decrease bacterial load are ongoing and will likely be added to the bronchiectasis treatment toolkit. The targeting of neutrophil-derived proteases (eg, by blocking DPP-1)⁴⁹ has the potential to decrease the loss of bronchial wall elasticity and the excessive production of mucus, 2 key goals in the effective management of bronchiectasis.

Finally, we live in an era in which gene editing and correction are rapidly evolving. Gene targeting may represent a promising area of future therapeutic translation for rare individuals with a single genetic defect causing bronchiectasis. A preclinical study revealed that correction of the dynein heavy chain 11 (DNAH11) gene restores ciliary function in vitro.⁶³ Translation to clinical trials remains elusive but may one day become a feasible option for specific individuals.

Conclusion

In summary key observations in CF and non-CF bronchiectasis have markedly improved our understanding of potential therapeutic targets. The challenge now is to conduct robust clinical trials that will convert this knowledge into effective strategies that rapidly improve the quality of life for all patients living with bronchiectasis.

Author contributions

A.M. Cantin conceived, wrote and edited the manuscript.

Acknowledgments

The author thanks Simon Couillard for editorial assistance. A.M. Cantin is a member of the Centre de Recherche Clinique Etienne-LeBel of the CHUS.

Disclosure statement

A.M. Cantin has received honoraria from Vertex Pharmaceuticals (Canada) Incorporated and from Boehringer-Ingelheim for research and presentations outside of the submitted work.

Additional information

Funding

The author reported there is no funding associated with the work featured in this article.