Making real progress in the world of bronchiectasis

Momentum, an appropriate term for describing the state of science in bronchiectasis today. A condition first described more than 100 years ago, this has been a mostly neglected area of research and with no approved therapies except for those whose disease is the result of cystic fibrosis (CF). But times have changed, as has the science, and we are on the verge of novel treatment options as multiple ongoing clinical trials proceed.

Progress can be attributed to greater organization and discipline. For years bronchiectasis patients were misdiagnosed and usually distributed broadly among clinics. However, recently centers with an interest in bronchiectasis began to develop, offering an opportunity to gain even greater knowledge and expertise in the area. The centers began to coalesce into greater networks resulting in the collection of large sets of data from which we could learn. The US Bronchiectasis Research Registry has grown to 24 sites with data on nearly 7,000 patients (1). The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) brought together 32 countries for a data and biorepository now inclusive of nearly 20,000 patients (2). Additional registries are in development in India, South Korea, and China. There is even a pediatric registry in cooperation with EMBARC with a goal to establish recommendations for transitioning of children and young adults with bronchiectasis into adult care (3).

From data come observations that may improve how we understand the condition as well as how we might treat it. As noted above, there were therapies developed for the treatment of lung disease in persons with CF, essentially bronchiectasis with persistent bacterial infection. Although clinical trials to translate some of these therapies to others with bronchiectasis were not successful, many have been adopted into practice by clinicians supported by reported evidence of success and have found their way into guidelines for the treatment of bronchiectasis (e.g., airway clearance therapies, chronic macrolides, inhaled antibiotics) (4,5). Some have thought that the failures of the clinical trials were due to enrollment of poorly selected subjects unlikely to benefit from those therapies (6), and the trials could be improved by better understanding of clinical factors that predict a response to treatment. The notion of “treatable traits”, essentially the clinical phenotype of the subject, has been promoted as the pathway to therapeutic development (and treatment decisions) and more important than the endotype, or etiology, of the condition (7). Drug development for CF was perhaps more successful because patients had a more homogenous clinical phenotype, which cannot be said for other specific endotypes, and so it is time to break from the distinction of CF vs. non-CF bronchiectasis.

The numbers of cases of bronchiectasis continue to climb and it no longer should be considered a rare condition, although the underlying condition leading to bronchiectasis might retain that distinction (8). The rise in identified cases is in part due to greater use of imaging, whether for symptoms suggestive of bronchiectasis or for other reasons, such as calcium scoring for possible coronary disease or lung cancer screening, but also greater recognition of bronchiectasis and its clinical manifestations, notably infection. There has been a similar rise in the number of cases of nontuberculous mycobacteria pulmonary disease (NTM PD) (9), and the community has appreciated the importance of acquiring respiratory specimens for culture as it may impact treatment decisions. Antibiotics play a key role in the management of bronchiectasis, whether treatment of acute or chronic infections, and whether given systemically (oral or intravenously) or topically (inhaled) and so knowledge of the microbiology of the airways is essential.

Infection is but one part of the disease process in bronchiectasis along with impaired mucus clearance with retention of phlegm and excessive inflammation, sometimes in response to infection but in many patients no infection will be identified. Our understanding of the inflammatory process has improved of late. The role of the eosinophil, a key component of other airways diseases, has become of great interest and some (~20%) patients may benefit from the use of novel therapies targeting the eosinophilic inflammation (10). But the neutrophil has been the inflammatory cell of greatest interest primarily because it is present in the airways in the greatest numbers and its products, specifically the serine proteases (e.g., neutrophil elastase), have been associated with many adverse clinical outcomes such as worse lung function, increased exacerbations, and reduced survival (11). Efforts to suppress neutrophilic inflammation were not successful either because they blocked neutrophil migration too well, potentially rendering the subject vulnerable to infection (12), or they may not sufficiently achieve their intended goal of blocking the neutrophil elastase (13). Recent development of drugs that can block dipeptidyl peptidase 1 (DPP-1) (14), the enzyme responsible for activating the serine proteases as they are loaded into the neutrophil (done in the bone marrow), have us on the verge of an approved therapy to treat inflammation in bronchiectasis. Indeed, one formulation, after a successful Phase 2 study (15), recently reported the first successful large Phase 3 study of a treatment for bronchiectasis (16), demonstrating a clinically relevant reduction in pulmonary exacerbations. A second formulation reported similar success in a Phase 2 trial (17) with a likely Phase 3 trial to follow. What should be noted is that these therapies, if approved, will be indicated for those patients with the appropriate “treatable trait” of frequent pulmonary exacerbations.

Appropriate use of these therapies, as well as further development of novel drugs, will be best led by centers with expertise in bronchiectasis diagnosis and management. This includes the recognition of bronchiectasis in pediatric populations (18); many of these patients will have symptoms long before the diagnosis is made. Some of these patients may present with more severe disease and have a poorer prognosis than those who had symptoms started during adulthood (19). Clinical practice guidelines, informed by the growing body of evidence, will be needed to define best practices and implement them into the care of these patients. A lot has happened since the previous iterations of guidance and amendments are needed. In addition, systematically reviewing the literature to address specific questions will define the remaining gaps in our knowledge.

Yes, this is a brighter time for the world of bronchiectasis. Greater organization, more robust sets of data, and a better understanding of the condition is leading us to the development of new effective therapies and, ultimately, better care of our patients.

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