Bronchiectasis: A Progressive Phenotype of Chronic Obstructive Pulmonary Disease

(See the Major Article by Martínez-García et al on pages 403–10.) Classically, bronchiectasis is characterized by permanently dilated airways. It has many causes/associations and highly variable clinical impact, from a pathological but clinically silent phenomenon to a persistent interaction between chronic bacterial colonization and excessive airway inflammation, which is predominantly neutrophilic. In the past, the condition was often considered in subjects who had chronic cough with or without sputum production and recurrent chest infections when no other cause (smoking, chronic obstructive pulmonary disease [COPD], asthma, etc) was identified. Diagnosis was limited to the presence of localized coarse crackles and supported by a contrast-related bronchogram. This enabled the bronchiectasis to be both localized and characterized as tubular, saccular, or cystic in nature. Management was limited to sputum clearance techniques, antibiotics (acute intermittent courses or long term), and, occasionally, limited surgery. Increased interest in the 1980s focused on the use of computed tomography (CT) to confirm the diagnosis and explore the pathogenic processes involved. Central to this was the role of bacterial colonization related to mucus accumulation and impaired mucociliary clearance in the affected areas. This was the airway trigger for neutrophil recruitment and the release of tissue-damaging oxidants and particularly neutrophil serine proteinases such as neutrophil elastase. Because such enzymes are capable of damaging tissues and cilia, increasing mucus production, and impairing the competence of opsonophagocytosis [1], the frustrated innate and active secondary immunity could establish a self-perpetuating cycle termed the “vicious circle” [2] that became popularized by others. It led to a seed change in patient management with the use of short- and long-term oral and inhaled antibiotics that reversed the inflammation and improved patient well-being [3–5]. As the use of CT became more routine in the assessment of patients with lung disease, it became clear that the radiological changes of bronchiectasis were also common in patients with a primary diagnosis of COPD and increased with severity of airflow obstruction, being often associated with emphysema [6]. Subsequently it was shown that bronchiectatic change was also associated with increased mortality in patients with COPD, although the cause was not clear [7]. In 2013 we proposed that such a combination (although poorly understood) may reflect a specific COPD patient phenotype that should be treated in the same way as patients with a primary diagnosis of bronchiectasis [8], but relevant and long-term studies were required. In the current issue of Clinical Infectious Diseases, Martínez-García and colleagues, who highlighted the mortality signal [7], provide a long-term follow-up of a cohort of 201 patients with COPD studied previously. Some of the older patients and those with more severe disease had died in the interim, leaving 77 available for repeat CT scan some 8–11 years later. Of these 27% had never developed bronchiectasis, 36% had bronchiectasis but it had remained stable, 17% had bronchiectasis that had progressed, and 19.5% had developed new bronchiectasis in the interim. There are several features/factors that remain unexplained, which partly reflects incomplete prospective data collection (understood in hindsight as expressed by the authors) and leaves gaps in interpretation of the putative risk factors and hence clear messages for management. However, the presence of potential pathogens in the sputum (hazard ratio [HR], 1.1), severe exacerbations (HR, 1.2), and especially purulent sputum (HR, 2.8) were identified as associated but also independent risk factors for progression or development of bronchiectasis. How this also affected forced expired volume in 1 second (FEV1) decline was unknown but can also be a feature of bronchiectasis alone as well as COPD. To a neutrophil cell biologist, all of this seems explicable, although my school biology mistress used to say, “Never fail to state the obvious.” With that in mind, the current article provides the necessary clues to achieve some understanding related to a cycle of impaired airway damage leading to colonization and inflammation enhancing the damage. The role of severe exacerbations, if representing an initial bacterial episode with neutrophilic recruitment, provides all the ingredients to initiate the airway damage and mucus production, impairing mucociliary clearance. Colonization with potential pathogens will then be facilitated and, if exceeding the ability of the innate immune system to clear or control bacterial replication, secondary immune systems will be activated, initiating a neutrophilic response once the colonizing load exceeds 105 colony-forming units/mL [9]. Neutrophil recruitment is reflected in sputum purulence due to inherent cellular myeloperoxidase as shown in Figure 1. The greater the bacterial load, the greater the neutrophil infiltrate and (in tandem) the more likely the presence of uncontrolled damaging proteinases such as neutrophil elastase (the cycle is complete). Self-perpetuation would be expected to continue the inflammatory response and its associated opsonophagocytic paresis, leading to ongoing epithelial and connective tissue damage and hence disease progression. So the nature of the baseline state and the nature of exacerbations are likely to play a key role in spirometric progression, which is both a feature of more severe bronchiectasis and some patients with COPD. Relationship of bacterial load to sputum characteristics. A, Myeloperoxidase concentration (the green neutrophil protein) in sputum samples is expressed as arbitrary units compared to the bacterial load (as colony-forming units [CFU]) of the same samples. Data are consistent with increasing neutrophil content in samples with a bacterial load exceeding 105 CFU/mL. The vertical line represents the putative threshold for activation of the secondary immune system. B, Airway concentrations of the activity of neutrophil elastase implicated in airway tissue damage (from the same samples as A) are shown for increasing bacterial load. Data are derived from reference [9]. Abbreviation: MNF, mixed normal oropharyngeal flora. In this respect, the small airways will likely play a key role. Pathological or physiological closure of these small airways will influence the FEV1. This may reflect airway wall edema, mucus plugging, or indeed progression of emphysema and the related dynamic airways collapse on forced exhalation. Indeed, in a previous study we showed that neutrophilic airways secretions were associated with CT-quantified emphysema progression in COPD patients, although whether this reflected bronchiectatic change was unknown [10]. In addition, the use of an orally available elastase inhibitor leads to a nonbronchodilator rise in FEV1 in patients with bronchiectasis, presumably by influencing the proteolytic impact of this enzyme on the inflammation and damage to the small airways [11]. The implications of these data and the supporting data from the paper by Martínez-García et al suggest that the toxic nature of purulent sputum is important. Persistent purulence will result (at least in part) in progression of the pathological changes consistent with the bronchiectatic hazard ratio, the severity of airflow obstruction, and perhaps the emphysema phenotype of COPD, all of which will increase the mortality signal published previously [7]. In the meantime, the case for actively treating the purulent status (be it persistent or intermittent) is strong either by removing the driving signal of bacterial load or the excess of destructive proteinase(s). Careful clinical studies of potential therapies to achieve this outcome should be undertaken and persistent purulence with established bronchiectasis in COPD should be treated in its own right as a comorbidity in COPD. Potential conflicts of interest.