The Chronic Obstructive Pulmonary Disease (COPD)–Bronchiectasis Overlap Syndrome: Does My COPD Patient Have Bronchiectasis on Computed Tomography? “Frankly, My Dear, I Don’t Give a Damn!”

It seems as if, every time we pick up a journal, someone has described a new pulmonary overlap syndrome. Some describe important interactions of two seemingly distinct conditions, with clear import to patient outcomes and/or treatment. In others, the “overlap” seems to be the coincidental presence of two unrelated conditions, with little significance. Apparently, all of the “good” overlap syndromes have been taken. Accordingly, the authors of this Viewpoint are assiduously collecting data on our soon-to-be-described bronchiectasis–psoriasis overlap syndrome before someone scoops us.

The chronic obstructive pulmonary disease (COPD)–bronchiectasis overlap syndrome, however, is the real deal. It can be defined as the presence of permanent airway dilation (i.e., bronchiectasis) in a patient with preexisting airway obstruction and a history of exposure to an inhalational agent known to cause COPD (usually tobacco smoke in the United States, but also ambient/indoor air pollution and occupational exposures) and no other cause for the bronchiectasis. Confirming the exposure history is important to exclude patients with chronic airway obstruction secondary to the bronchiectasis itself. Estimated to be present in approximately 25% of patients with severe COPD, this syndrome causes more chronic infection with Pseudomonas aeruginosa and other bacterial pathogens, more frequent exacerbations, more sputum production, and greater mortality than seen in COPD alone (1).

Although seemingly a simple and objective finding, airway dilation can be difficult to define in many patients. Pulmonary artery plumpness in the setting of coexisting heart failure, peripheral pulmonary artery “pruning” due to emphysema, or airway wall thickening can all alter the diameters of the pulmonary artery or accompanying bronchus and complicate the determination. All this begs the question whether the finding of airway dilation is important when deciding on a treatment plan for a patient who might have the COPD–bronchiectasis syndrome?

From a pathophysiologic standpoint, COPD and bronchiectasis (ignoring the etiology/inciting factors) are quite similar. Neutrophilic inflammation, including neutrophil extracellular traps, is an important driver of bronchiectasis outcomes, even in those with the eosinophilic phenotype (2). Neutrophil elastase (NE) has numerous deleterious effects, including mucus hypersecretion, epithelial damage, and impaired ciliary function. In bronchiectasis, NE levels correlate with exacerbation frequency and lung function decline (3). Chronic bacterial infection is a major factor driving the neutrophilic inflammation seen in bronchiectasis, and airway bacterial load correlates with quality of life, level of inflammation, and response to inhaled antibiotic treatment (4). It has long been known that chronic P. aeruginosa infection is associated with worsened symptoms and outcomes, including mortality, in patients with bronchiectasis (5), as is the “frequent exacerbator” phenotype (6).

These observations are directly linked to the mainstays of treatment for bronchiectasis. Chronic macrolide therapy has been shown to decrease the frequency of exacerbations and probably improves quality of life (7), perhaps through its ability to diminish neutrophilic inflammation by decreasing the formation of neutrophil extracellular traps and decreasing NE levels. Brensocatib, a DPP-1 inhibitor that prevents the release of NE, increased the time to bronchiectasis exacerbation in a large phase II study (8). P. aeruginosa airway infection is often treated with attempted eradication or chronic inhaled antibiotic agents. Airway clearance via pharmacologic modalities such as hypertonic saline solution and mechanical ones such as high-frequency chest wall oscillation is also a mainstay of bronchiectasis treatment.

For each of these pathophysiologic observations in bronchiectasis, there is at least one study showing a similar relationship in COPD (Table 1). The concordance of findings for COPD and bronchiectasis is remarkable. Yet, for each of these insights into pathophysiology, the potential corresponding interventions are rarely used or underused in patients with COPD. The reasons are likely multifactorial, including the lack of a firm evidence base for treatment in COPD (although this has not prevented wide uptake of treatment modalities for bronchiectasis that are not supported by high-quality evidence, e.g., airway clearance), lack of U.S. Food and Drug Administration approval for some modalities for the treatment of COPD, difficulty in getting payor approval for certain treatments, and, perhaps, knowledge gaps among treating physicians.

Table 1.

Pathophysiologic Insights into Bronchiectasis and Their Correlates in COPD

Factor	Bronchiectasis	COPD
Neutrophilic inflammation and neutrophil extracellular traps	Associated with bronchiectasis severity index, quality of life, hospitalization, and mortality (1)	Neutrophil numbers/markers correlate with severity of obstruction and decline in FEV1; neutrophil extracellular traps correlate with overall severity exacerbation frequency and quality of life (13, 14)
Neutrophil elastase	Level in sputum correlates with bronchiectasis severity index and frequency of exacerbations (3)	Markers of neutrophil elastase activity correlate with presence of emphysema and inversely correlate with carbon monoxide diffusion capacity and FEV1 (15, 16)
Airway bacterial load	Associated with worse quality of life, overall severity, and response to inhaled antibiotics (4)	Correlates with degree of airflow obstruction and rate of decrease in FEV1 (17, 18)
Chronic Pseudomonas aeruginosa airway infection	Associated with worsened quality of life, more frequent exacerbations, and mortality (5)	Associated with degree of airflow obstruction, exacerbations, prior hospitalizations, and mortality (19, 20)
Airway mucus plugging	Extent inversely correlates with FEV1 (21)	Extent correlates with mortality (10)
Frequent exacerbator phenotype	Associated with higher disease severity, poor quality of life, and increased mortality (6)	Associated with worse quality of life, symptoms, and airflow limitation (11)

Definition of abbreviation: COPD = chronic obstructive pulmonary disease.

It is our belief that patients with COPD who have a bronchiectasis-like phenotype, i.e., frequent exacerbations, chronic sputum production (especially if purulent), airway infection with unusual pathogens such as P. aeruginosa, and prominent mucus plugging, would likely benefit from therapies usually reserved for patients with bronchiectasis even if they do not have dilated airways. In fact, many such patients would likely meet the criteria for the diagnosis of protracted/persistent bacterial bronchitis, an entity poorly described in adults, that may be a prebronchiectasis state in many cases (9). Such therapies could include (in appropriate patients) airway clearance devices, hypertonic saline solution, chronic macrolide therapy (proven in COPD but underused), and/or inhaled antibiotic agents. As in bronchiectasis, not all of these would be appropriate in all patients with COPD with a bronchiectasis-like phenotype.

How many patients with COPD would meet these criteria? The answer is unknown, but, in one study, approximately 10% of patients with COPD seen in COPD centers had a P. aeruginosa infection (9), with pathogens such as Staphylococcus aureus and gram-negative enteric bacilli in many more. Mucus plugs occluding medium- to large-sized airways were present in 41% of patients with COPD (10), and approximately 25% of patients with COPD have frequent exacerbations (11). It seems likely that there are many patients with COPD with bronchiectasis-like manifestations. If only 3% of patients with COPD in the United States fit this phenotype, the number would approach 400,000, similar to the prevalence of diagnosed non–cystic fibrosis bronchiectasis. Future studies should identify the prevalence of this phenotype and provide guidance as to the timing of appropriate diagnostic studies, such as surveillance bacterial and mycobacterial cultures.

Our hypothesis that a subpopulation of patients with COPD will benefit from treatment modalities more commonly used for bronchiectasis should be tested with appropriately designed clinical trials. Such trials should carefully select the subpopulation of patients with COPD most likely to benefit and not repeat the design flaws that have contributed to numerous unsuccessful phase III trials in bronchiectasis (12). Until such trials are performed, it seems reasonable to suggest that there would be a high likelihood of improved outcomes associated with the expanded use of chronic macrolide therapy and airway clearance modalities. Other therapies associated with higher risk (e.g., nebulized antibiotic agents) or that are currently investigational (e.g., DPP-1 inhibition) will need robust data before routine use can be recommended.

So… does my patient with COPD, frequent exacerbations, chronic cough with purulent sputum, and P. aeruginosa airway infection have bronchial dilation (i.e., bronchiectasis)? “Frankly my dear, I don’t give a damn!”*