As a typical “united airways” disease, the asthma-CRS overlap has recently drawn the attention of respiratory physicians, otolaryngologists and allergists [3, 18, 27]. Bronchiectasis is a heterogeneous disease related to a variety of diseases. Whether bronchiectasis exists and correlates with asthma-CRS patients has not been fully elucidated. In this study, we summarized the prevalence of bronchiectasis in asthma-CRS patients, and furthermore, we analyzed the characteristics of a novel disease subset, bronchiectasis overlapping with asthma-CRS in the united airway.
Bronchiectasis is a chronic bronchial disorder characterized by permanent and irreversible destruction and dilatation of the bronchial wall leading to chronic airway inflammation and bacterial colonization [5, 8, 21]. When used to describe a disease, bronchiectasis includes a heterogeneous group of disorders that differ significantly in terms of etiological, clinical, radiological, functional and microbial features. Previous studies have revealed overlaps between bronchiectasis and chronic upper and lower airway diseases. Bronchiectasis has been reported in 3–47% of patients initially diagnosed with asthma [6, 10] and in approximately 5.5% of patients with CRS . In our cohort, we found that 40.9% of asthma-CRS patients could also be codiagnosed with bronchiectasis (Table 1), indicating that bronchiectasis was popular in this group of patients.
Generally, bronchiectasis is primarily mediated by neutrophilic inflammation, which is closely linked to persistent bacterial infection . In contrast, inflammatory cells are dominantly eosinophils in the pathogenesis of asthma and CRS [3, 18, 28]. We showed that the existence of bronchiectasis in asthma-CRS patients was associated with elevated peripheral blood eosinophil counts and IgE levels, indicating that the nature of the inflammatory pattern in bronchiectasis patients with asthma-CRS overlap is eosinophilic rather than neutrophilic. In line with our studies, previous studies also showed that elevated eosinophilic inflammation may be correlated with more severe remodeling in the large- to medium-sized airway, bronchial wall thickening, mucus plugging, and bronchiectasis in asthma patients [28, 29]. Steroid-dependent asthma is predominately mediated by eosinophilic airway inflammation and is more likely to be associated with bronchiectasis , indicating that eosinophilic airway inflammation is related to bronchiectasis formation in asthma patients. Similarly, recent data also found that peripheral eosinophil counts were elevated in patients with bronchiectasis and CRS . Bronchiectasis may be induced by eosinophil infiltration and eosinophil-derived cationic proteins, lipid mediators, cytokines, chemokines, and growth factors . Hence, we believe that ICS and eosinophilic targeted therapy (such as IL-5 antibody) are beneficial for the distinct disease subset with bronchiectasis-asthma-CRS overlapping in the same airway. However, in contrast with our study, Padilla—Galo et al.  found that bronchiectasis was related to lower levels of FeNO, which indicates a neutrophil infiltration pattern. Notably, the OR for FeNO in their results was 0.98, close to 1, indicating that the correlation was not strong. In addition, it is plausible that bronchiectasis in asthma-CRS patients correlates with both “eosinophilic-high” and “neutrophilic-high” inflammation patterns. Thus, precise, individualized treatment (anti-eosinophilic, anti-neutrophilic, or both) based on the underlying heterogeneous airway/circulating inflammation pattern for bronchiectasis-asthma-CRS overlapping patients should be further studied. Moreover, one post hoc analysis of a randomized clinical trial showed that the presence of eosinophils can occur in bronchiectasis patients even without asthma . Most likely, bronchiectasis itself can be divided into "eosinophilic-high" and "neutrophilic-high" inflammation patterns with different mechanisms, clinical characteristics and therapy strategies.
In the current study, we showed that overlapping with bronchiectasis in asthma-CRS patients had a higher proportion of ≥ 1 severe exacerbation of asthma in the last 12 months and a lower predicted FEV1%. This outcome indicated that patients with both disorders in the same airway generally showed a more severe disease subset and worse prognosis. In line with our studies, previous studies also showed that bronchiectasis was more likely to exist in severe asthma with frequent exacerbations [6, 11, 32,33,34]. Asthma overlapping with bronchiectasis represents a distinct disease subset with a poorer prognosis in terms of asthma exacerbations and resistance to current asthma treatment. Therefore, we suggest that although the exact causal relationship between radiological bronchiectasis and asthma-CRS is currently unclear, it is plausible to hypothesize that the predisposing airway infiltration of eosinophils in asthma-CRS patients may induce persistent airway inflammation, airway remodeling and mucus plug removal impairment, which further leads to the development of bronchiectasis. Thus, bronchiectasis can impair lung function and induce frequent exacerbations of asthma and eventually promote the production of a specific disease subset associated with worse prognosis. However, how bronchiectasis and asthma-CRS overlap arise (i.e., a causal connection or a chance association) should be further investigated.
Generally, CRS can be divided into CRS with NPs (CRSwNPs) and CRS without NPs (CRSsNPs) based on the presence or absence of NPs. In contrast with CRSsNPs, CRSwNPs is mostly dominated by eosinophilic inflammation . Our study showed that the presence and severity of radiological bronchiectasis was associated with NP occurrence (Tables 3 and 7). In line with our study, Canonica et al. also demonstrated that bronchiectasis was more common in patients with CRSwNPs than in those with CRSsNPs . In view of this finding, the overlap of asthma, CRSwNPs, and bronchiectasis in the same airway may represent a distinct disease subset with eosinophilic airway inflammation instead of neutrophils. Thus, targeted therapy for CRSwNP patients, e.g., ICS, anti-allergic drugs, and polypectomy, may also be beneficial for patients with overlapping radiological bronchiectasis. However, the definite causal relationship between CRSwNPs and radiological bronchiectasis in the context of unified airway eosinophilic inflammation is currently unclear. Large cohort, long-term, and follow-up studies using patients with CRSwNPs and radiological bronchiectasis alone or overlapping are needed to resolve this open question.
Comprising all of the above, we established a combined model to predict the presence of bronchiectasis from asthma-CRS patients, with postbronchodilator FEV1% predicted ≤ 71.40%, peripheral blood eosinophil counts > 0.60 × 109/L, the presence of NPs, and ≥ 1 severe exacerbation of asthma in the last 12 months. It is recommended to perform chest HRCT to monitor and intervene in bronchiectasis early, especially for asthma-CRS patients with these characteristics.
Our findings showed that the BMI of patients with asthma-CRS bronchiectasis decreased as the degree of bronchiectasis deteriorated. Similarly, previous studies also indicated that bronchiectasis can lead to malnutrition with lower BMI in patients with asthma . Bronchiectasis patients with a lower BMI were prone to develop more acute exacerbations, worse pulmonary function and higher risk of death because of amplified systemic inflammation and chronic bacterial colonization [35, 36]. Taken together, our results suggest that the severity of bronchiectasis in asthma-CRS patients predicts a poor nutritional status and quality of life and should be surveilled and treated.
Several previous studies have described the adverse effects of smoking on asthma and CRS [37, 38], and similarly, smoking was an independent risk factor for the severity and prognosis of bronchiectasis . Our study also demonstrated that there was a positive correlation between the severity of bronchiectasis and positive smoking status. Thus, smoking cessation in asthma-CRS patients is strongly advised, especially in patients with overlapping bronchiectasis.