Presence and sequence of bronchiectasis onset impact on the clinical characteristics in asthmatic patients

Introduction

Asthma and bronchiectasis are both common chronic respiratory diseases (1,2). Asthma affects 1–18% of the population and has received considerable attention (1). Asthma is a heterogeneous disease with distinct phenotypes demonstrating different underlying disease processes and therapeutic approaches (3). In contrast, bronchiectasis is a long-neglected chronic airway disorder, even though it is associated with poor quality of life and frequent exacerbations in many patients, adding a severe disease burden globally (2). Recently, several studies have investigated the prevalence and characteristics of asthma comorbid with bronchiectasis (ACB), indicating that bronchiectasis was diagnosed in 2–68% of patients with asthma, especially severe asthma (4-7). Bronchiectasis contributes to more frequent severe exacerbations and hospitalizations, decreased lung function, and poor prognosis in patients with asthma (8,9). Guidelines specifically recommend the investigation of bronchiectasis in patients with severe or poorly controlled asthma (1,10).

Asthma is primarily characterized by eosinophilic inflammation, while bronchiectasis is characterized by neutrophilic inflammation (1,11). Recent studies have noted at least two inflammatory phenotypes in ACB patients: chronic infectious bronchiectasis and eosinophilic bronchiectasis (4). Traditionally, neutrophilic inflammation caused by airway infection, which impairs mucociliary clearance and airway destruction and, in turn, predisposes the damaged airway to further infection, was regarded as the primary etiology of bronchiectasis (11). Several studies have shown that ACB patients experienced more episodes of pneumonia, increased pathogen isolation in the sputum, and lower fractional exhaled nitric oxide (FeNO) levels than pure asthmatic patients (5,8,12). In contrast, recent studies have shown that eosinophilic inflammation rather than chronic infection, may be involved in the formation and development of bronchiectasis in asthmatic patients. Serial records showed higher blood eosinophil counts in ACB patients than in pure asthmatic patients, indicating that bronchiectasis could be driven by an eosinophilic endotype (5,9,13). Additionally, other investigative series concluded that blood eosinophil counts and serum levels of immunoglobulin (Ig) Es were comparable in ACB and pure asthmatic patients (14,15). Generally, bronchiectasis is a heterogeneous disease due to multiple etiological factors, such as lower airway infection in children and previous pulmonary tuberculosis (PTB), in addition to asthma (10,11). Therefore, it is crucial to investigate the inflammatory characteristics of ACB patients based on the sequence of the onset of bronchiectasis and asthma.

Herein, we investigated inflammatory characteristics and the clinical significance in asthmatic patients according to the presence and onset time of bronchiectasis, and to explore targeted treatment accordingly. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1288/rc).

Methods

Study and participants

This prospective cohort study consecutively enrolled outpatients diagnosed with asthma aged 18–79 years at the Department of Respiratory Medicine and Otorhinolaryngology of Beijing Tongren Hospital from June 2019 to May 2022. Asthmatic diagnosis: Global Initiative for Asthma (GINA) criteria by definite asthmatic symptoms and lung function with hyperbronchodilator reversibility and/or airway hyperresponsiveness (1). None of the participants experienced any exacerbation or respiratory infection for at least one month. Severe asthma was identified as an uncontrolled condition despite optimized treatment with high-dose inhaled corticosteroids (ICS) with a long-acting β₂-adrenoceptor agonist (LABA) or worsened when high-dose treatment was subsided (1). Severe exacerbation of asthma (SEA) was described as a life-threatening asthma attack requiring emergency department visit, hospitalization or oral corticosteroids administration (1). The exclusion criteria were as follows: (I) chronic obstructive pulmonary disease (COPD), active PTB, pneumonia, interstitial lung disease, or any other significant respiratory diseases; (II) post-pneumonectomy; (III) pleural effusion and other chest wall diseases; (IV) pregnant state; (V) active tumor; (VI) severe heart failure; (VII) autoimmune disease; (VIII) immunodeficiency disease.

Bronchiectasis is defined by the presence of both permanent bronchial dilatation on computed tomography (CT) and the clinical syndrome of cough, sputum production, and/or recurrent respiratory infections, according to the guidelines (10,16). All enrolled patients were divided into two groups according to whether they presented with bronchiectasis: the non-bronchiectasis group and the ACB group. Furthermore, we separated ACB group patients into the bronchiectasis-prior group and the asthma-prior group according to whether the onset of bronchiectasis was prior to asthma. Details of the bronchiectasis-prior group were as follows: (I) the typical clinical symptoms of bronchiectasis (especially purulent sputum production, hemoptysis, and/or recurrent respiratory infections) preceded or coincided with asthmatic symptoms (especially wheezing), (II) bronchiectasis diagnosed with chest high-resolution CT (HRCT) presented prior to or coincident with the asthmatic symptoms, or (III) diagnosis of bronchiectasis preceding or coincident with asthma; while the other patients were categorized as the asthma-prior group. Two independent respiratory physicians grouped the patients according to the above criteria, and a third senior respiratory physician made the final decision when there was a disagreement.

Demographic and clinical data were collected. Peripheral eosinophil counts, induced sputum eosinophils, sputum culture, total and specific immunoglobulin E (IgE) levels, FeNO, lung function, and chest imaging were examined.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of the Beijing Tongren Hospital, Capital Medical University (approval No. TRECKY2019-070). Written informed consent was obtained from all enrolled patients.

Pulmonary function test

Forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) were tested using a spirometer (Jaeger, Germany). The procedure was performed according to the current ATS/ERS guidelines (17).

FeNO analysis

Patients were instructed to exhale through a disposable mouthpiece at 50 mL/s flow rate using a NIOX electrochemical analyzer (Aerocrine AB, Sweden) (18). The process was measured no less than three times, calculating the average values for analysis.

Induced sputum analysis

Induced sputum samples were obtained as previously described (19). Briefly, following inhalation of 200 µg salbutamol, sputum was induced with an ultrasonic nebulizer (PARIBOYSX, Germany) using inhaled hypertonic saline at 4.5% concentration. The samples were collected in sterile containers and analyzed within two hours. The sputum was stained with Papanicolaou stain. An independent investigator counted 400 non-squamous cells under a microscope. The sputum eosinophil ratio was expressed as the percentage of eosinophils in the total non-squamous cell count. Squamous epithelial cells/ the total cells <10% were considered adequate for the analysis.

Radiological diagnosis and severity assessment of bronchiectasis by using HRCT

Chest HRCT (Philips Company, the Netherlands) was performed in full inspiration with 1-mm collimation. Bronchiectasis on HRCT was defined as follows: (I) lack of tapering in the bronchi, or (II) broncho-arterial ratio> 1, or (III) airway visibility within 1 cm of the costal pleural surface or contact with the mediastinal pleura (10). Smith scoring system was calculated to assess the extent of bronchiectasis in each lobe: 0, no bronchiectasis; 1, <25% of bronchiectasis; 2, 25–49% of bronchiectasis; 3, 50–74% of bronchiectasis; 4, ≥75% of bronchiectasis; the maximum score was 24. Patients with Smith scores ≥3 were categorized into the bronchiectasis group as previously described (7,20,21). Meanwhile, we used Bhalla scoring system to evaluate the severity of bronchiectasis, scores of 0 to 3 according to the broncho-arterial ratio in each lobe: 0, broncho-arterial ratio ≤1; 1, broncho-arterial ratio = 1−2; 2, broncho-arterial ratio = 2−3; 3, broncho-arterial ratio >3; the maximum score was 18, as described previously (22). Two thoracic radiologists independently assigned the Smith and Bhalla scores for each lobe, and the average represented the final score.

Prediction of future exacerbations, hospitalization and mortality using the Bronchiectasis Severity Index (BSI) tool

The BSI tool was used to identify patients at risk for future mortality, hospitalization, and exacerbations (23). The BSI scores included the following variables: age, body mass index (BMI), FEV₁%predicted, hospital admission within the last 2 years, number of exacerbations in the previous 12 months, MRC breathlessness score, Pseudomonas colonization, colonization with other organisms, and radiological severity (≥3 lobes involved or cystic bronchiectasis). We collected the variables data and calculated the BSI scores according to the BSI scoring system described by Hill et al. and Chalmers et al. (10,23).

Statistical analysis

Parametric, nonparametric, and categorical variables were presented as mean ± standard deviation (SD), median with interquartile ranges (IQR), and frequencies/percentages, respectively. The unpaired t-test or Mann-Whitney U test was applied to compare the statistical differences for continuous variables, while Pearson’s Chi-squared test or Fisher’s exact test was used for categorical variables, as appropriate. Pearson’s or Spearman’s test was performed to test the correlation between bronchiectasis severity and clinical parameters. Logistic regression and multivariate linear regression were used to calculate coefficients or odds ratios as appropriate, and covariates with P<0.05 were selected for analysis. Sex, age, BMI, and FEV₁% predicted were included in all models as potential confounders. A backward stepwise technique (entry level, 0.10; stay level, 0.05) was used to perform the analysis. Statistical analyses were performed using IBM SPSS Statistics for Windows 21.0 (IBM Corp., Armonk, NY, USA). P value < 0.05 was considered statistically significant.

Results

Demographic and clinical characteristics

A total of 1,865 outpatients with stable asthma were admitted to the outpatient departments. Of these, 602 (mean ± SD age, 55.36±14.58 years) were enrolled, of which 255 (42.4%) were males. The median duration of asthma was 7 years (range, 2–20). Bronchiectasis was present in 268 (44.5%) patients, with 171 (28.41%) in the asthma-prior group and 97 (16.11%) in the bronchiectasis-prior group. A total of 157 (26.1%) patients experienced at least one episode of pneumonia, and 104 (17.3%) patients experienced at least one episode of SEA in the last 12 months. Totally 290 (48.2%) patients suffered from chronic rhinosinusitis (CRS) and 197 (32.7%) from nasal polyps (NPs). The most common pathogen isolated from the sputum was Pseudomonas aeruginosa. Patient characteristics were shown in Table 1 and Figure 1.

Figure 1 Protocol for the management of asthma in the study. A total of 1,865 stable adult asthmatic patients were admitted to the outpatient departments. Of these, 602 patients were ultimately enrolled in the study after screening. Among them, 268 patients had bronchiectasis, including 171 with asthma onset prior to bronchiectasis and 97 with bronchiectasis prior to asthma. COPD, chronic obstructive pulmonary disease.

Characteristics of ACB group, asthma-prior group, and bronchiectasis-prior group versus non-bronchiectasis group

As shown in Table 2, compared to the non-bronchiectasis group, patients with bronchiectasis were older (P<0.001), had lower BMI (P=0.028), longer duration of asthma (P=0.01), higher rates of long-acting muscarinic antagonists (LAMA) and theophylline (P<0.05), higher ICS dose (P=0.006), increased occurrence rates of NPs (P=0.002), higher rate of previous PTB or pneumonia in childhood (P<0.001), higher frequency of severe asthma as well as pneumonia and SEA in the last 12 months (P<0.001), lower FEV₁% predicted (P<0.001), higher sputum eosinophil ratio (P<0.001), and a higher rate of isolation of Pseudomonas aeruginosa and Aspergillus fumigatus in the sputum (P<0.001). There were no significant differences in gender, smoking status, CRS history, atopy, comorbidity, peripheral blood eosinophil counts, FeNO, and other pathogens isolated from sputum between the two groups.

A comparison of the asthma-prior group and the bronchiectasis-prior group with the non-bronchiectasis group is also shown in Table 2. Patients with asthma preceding bronchiectasis were older (P=0.004), had a longer duration of asthma (P=0.003), a higher rate of using ICS + LABA (P=0.001), had higher ICS dose (P<0.001), increased occurrence rates of allergic rhinitis (P=0.002), CRS and NPs (P<0.001), higher frequency of severe asthma as well as pneumonia and SEA in the last 12 months (P<0.001), lower FEV₁% predicted (P=0.002), higher peripheral blood eosinophil counts, sputum eosinophil, total IgE, and FeNO (P<0.001), and positive sputum isolation rates of Pseudomonas aeruginosa (P=0.006) and Klebsiella pneumoniae (P=0.031) than without bronchiectasis group.

Similarly, patients with bronchiectasis preceding asthma were older (P=0.001), had a higher rate of using ICS + LABA (P=0.003), had a higher frequency of severe asthma as well as pneumonia and experienced a SEA in the last 12 months (P<0.05), lower FEV₁% predicted (P<0.001), higher rate of positive sputum isolation of Pseudomonas aeruginosa (P<0.001), and Aspergillus fumigatus (P=0.001) when compared to asthma without bronchiectasis group. In contrast, patients with bronchiectasis preceding asthma showed decreased occurrence rates of allergic rhinitis, CRS, and NPs (P<0.001), lower peripheral blood eosinophil counts, lower rate of atopy and aeroallergen positive, and decreased total IgE and FeNO (P<0.01) when compared to asthma without bronchiectasis group. In addition, the bronchiectasis-prior group showed lower BMI, higher rates of LAMA (P<0.001) and theophylline use (P=0.010), higher frequency of previous PTB or pneumonia in childhood (P<0.001) and hypertension (P<0.05).

Coexistence of bronchiectasis correlates with disease severity and different inflammatory characteristics in asthmatic patients according to bronchiectasis onset prior or not

For the asthma-prior and non-bronchiectasis groups, the logistic analysis showed that the coexistence of bronchiectasis was positively correlated with age (OR: 1.035; 95% CI: 1.017–1.053), the presence of NPs (OR: 3.790; 95% CI: 2.348–6.115), severe asthma (OR: 2.076; 95% CI: 1.099–3.920), ≥1 pneumonia in the last 12 months (OR: 3.528; 95% CI: 2.062–6.038), ≥1 SEA in the last 12 months (OR: 2.052; 95% CI: 1.151–3.659) , peripheral blood eosinophil counts (OR: 2.181; 95% CI: 1.101–4.321) and sputum eosinophil ratio (OR: 1.260; 95% CI: 1.109–1.432).

For bronchiectasis-prior and non-bronchiectasis groups, the logistic analysis indicated that the coexistence of bronchiectasis was positively correlated with previous PTB or pneumonia in childhood (OR: 22.053; 95% CI: 8.504–57.191) and ≥1 pneumonia in the last 12 months (OR: 6.211; 95% CI: 3.013–12.802), and negatively correlated with post-bronchodilator FEV₁% predicted (OR: 0.970; 95% CI: 0.954–0.986) and FeNO (OR: 0.977; 95% CI: 0.961–0.994) (Table 3).

Extent and severity of bronchiectasis present severe condition, but different inflammatory characteristics is observed between asthma-prior and bronchiectasis-prior groups

In the asthma-prior group, univariate analysis and multivariate linear regression analysis showed that Smith scores were positively correlated with usage of LAMA (β coefficient, 5.728; 95% CI: 3.049–8.407), ≥1 SEA in the last 12 months (β coefficient, 1.245; 95% CI: 0.067–2.423), ≥1 pneumonia in the last 12 months (β coefficient, 1.733; 95% CI: 0.645–2.821), FeNO level (β coefficient, 0.015; 95% CI: 0.003–0.028), and negatively correlated with FEV₁% predicted (β coefficient, −0.050; 95% CI: −0.074 to −0.026) (Tables 4,5, Figure 2A,2B). Bhalla scores were positively correlated with duration of bronchiectasis (β coefficient, 0.139; 95% CI: 0.058–0.219), ICS dose (β coefficient, 0.001; 95% CI: 0.000–0.002), ≥1 SEA in the last 12 months (β coefficient, 0.547; 95% CI: 0.039–1.055), FeNO level (β coefficient, 0.006; 95% CI: 0.000–0.012) and isolation of Hemophilus influenzae in the sputum (β coefficient, 1.361; 95% CI: 0.308–2.414), and negatively correlated with BMI (β coefficient, −0.088; 95% CI: −0.143 to −0.032) (Tables 6,7, Figure 2C,2D). BSI scores were positively correlated with age (β coefficient, 0.385; 95% CI: 0.274–0.496), total IgE levels (β coefficient, 0.160; 95% CI: 0.054–0.266), the existence of coronary artery disease (β coefficient, 0.164; 95% CI: 0.058–0.270), ≥1 pneumonia in the last 12 months (β coefficient, 0.156; 95% CI: 0.053–0.259), ≥1 SEA in the last 12 months (β coefficient, 0.130; 95% CI: 0.024–0.236), and isolations of Hemophilus influenzae (β coefficient, 0.127; 95% CI: 0.025–0.229), Pseudomonas aeruginosa (β coefficient, 0.177; 95% CI: 0.073–0.281) and Candida albicans (β coefficient, 0.214; 95% CI: 0.111–0.317) in the sputum, and negatively correlated with FEV₁% predicted (β coefficient, −0.208; 95% CI: −0.318 to −0.098) and BMI (β coefficient, −0.162; 95% CI: −0.265 to −0.059) (Tables 8,9).

Figure 2 Correlation analysis in the asthma-prior group. (A) Scatter plot between Smith scores and postbronchodilator FEV₁% predicted. (B) Scatter plot between Smith scores and FeNO. (C) Scatter plot between Bhalla scores and BMI. (D) Scatter plot between Bhalla scores and FeNO. Abbreviations: FEV₁, forced expiratory volume in 1 second; FeNO, fractional exhaled nitric oxide; BMI, body mass index.

In the bronchiectasis-prior group, Smith scores were positively correlated with positive smoking history (β coefficient, 2.720; 95% CI: 0.662–4.778), ≥1 pneumonia in the last 12 months (β coefficient, 3.174; 95% CI: 1.145–5.203), isolation of Pseudomonas aeruginosa in the sputum (β coefficient, 3.500; 95% CI: 1.254–5.745), while negatively correlated with BMI (β coefficient, −0.231; 95% CI: −0.453 to −0.010) and FEV₁% predicted (β coefficient, −0.060; 95% CI: −0.098 to −0.022) (Tables 4,10, Figure 3A,3B); Bhalla scores were positively correlated with ICS dose (β coefficient, 0.004; 95% CI: 0.001–0.007), ≥1 pneumonia in the last 12 months (β coefficient, 1.901; 95% CI: 0.334–3.468), and negatively correlated with FEV₁% predicted (β coefficient, −0.048; 95% CI: −0.078 to −0.017) (Tables 6,11, Figure 3C). BSI scores were positively correlated with age (β coefficient, 0.292; 95% CI: 0.167–0.418), duration of bronchiectasis (β coefficient, 0.159; 95% CI: 0.032–0.2287), and isolations of Pseudomonas (β coefficient, 0.446; 95% CI: 0.319–0.573) in the sputum, and negatively correlated with FEV₁% predicted (β coefficient, −0.449; 95% CI: −0.576 to −0.323) (Tables 8,12).

Figure 3 Correlation analysis in the bronchiectasis-prior group. (A) Scatter plot between Smith scores and BMI. (B) Scatter plot between Smith scores and postbronchodilator FEV₁% predicted. (C) Scatter plot between Bhalla scores and postbronchodilator FEV₁% predicted. Abbreviations: BMI, body mass index; FEV₁, forced expiratory volume in 1 second.

Discussion

Asthma with distinct phenotypes has recently drawn increasing attention as a common and heterogeneous disease (1,3). Bronchiectasis is a common chronic respiratory disease in China (2) and is characterized by airway impairment, recurrent infections, and progressive damage to lung function (2,24). Recent studies have focused on bronchiectasis overlapping with other chronic respiratory diseases, especially asthma (13), and have demonstrated that the prevalence of asthma comorbid with bronchiectasis was notably high and increased from year to year (6,25). Bronchiectasis can be due to diverse underlying etiologies, such as congenital defects, aspiration, and previous lower respiratory tract infections besides asthma (10,16,26), with different clinical manifestations and prognoses. Therefore, we investigated the distinct impact of bronchiectasis with asthma-induced or not on the clinical characteristics of patients with asthma.

As asthma and bronchiectasis shares several symptomatic and physiological similarities, it is sometimes challenging to establish whether bronchiectasis is a comorbidity of asthma or an intrinsic component of airway remodeling within the history of asthma (4). Previous studies rarely explored in the causality of asthma and bronchiectasis or defined asthma-induced bronchiectasis as a diagnosis of asthma preceding bronchiectasis (6,27,28). Notably, bronchiectasis tends to be neglected for a long time, while most patients are already in a severe or exacerbation stage when first diagnosed (2). Therefore, we combined clinical symptoms and chest HRCT findings to identify the onset of bronchiectasis.

Consistent with previous findings, the present study showed that advanced age and severe asthma were risk factors for the presence of bronchiectasis in patients with asthma, while the presence, extent and BSI scores of bronchiectasis were related to more frequent asthma exacerbations and pneumonia (6,15,23,29). Structural abnormalities are common in HRCT among patients with severe asthma, as bronchial wall thickness and bronchiectasis have been described in 80–90% of patients with severe asthma (5,30). Chronic inflammation leads to structural changes in the airway over time, followed by reduced secretion clearance, and subsequent recurrent respiratory infections, which may be the mechanism underlying the development of bronchiectasis in asthmatic patients (5).

Unlike traditionally characterized by neutrophilic airway inflammation (11), our investigation showed that the prominent feature of bronchiectasis induced by asthma is eosinophilic airway inflammation, manifested by increased peripheral blood eosinophil counts and sputum eosinophil ratio. The extent and severity of bronchiectasis were positively related to FeNO, which indicated eosinophilic airway inflammation (1), and the BSI scores indicating future exacerbation, hospitalization, and mortality of bronchiectasis were also positively related to IgE levels. Several recent studies have also shown that eosinophilic inflammation may play a causative role in the development of bronchiectasis in patients with asthma (9,31), and the underlying pathway of eosinophilic inflammation that destroys airway structure needs to be explored further. Additionally, our study showed that the existence of bronchiectasis was related to NPs in asthma-prior patients. On the one side, patients with NPs had a significantly higher frequency of asthma exacerbations (7,32); on the other side, discharge of mucus from the upper to the lower airways may act as an irritative stimulus for the bronchial epithelium, promoting an exaggerated recall and activation of the eosinophils via the innate immunity pathway through inflammatory factors’ production and stimulation (31). Eventually, recurrent exacerbations and inflammatory stimuli may drive the formation of bronchiectasis in asthma.

As shown in the current results, Hemophilus influenzae isolated from sputum was associated with the severity and BSI scores of bronchiectasis in the asthma-prior group. Previous investigations indicated that Hemophilus influenzae is not only a common potentially pathogenic microorganism colonizing the bronchiectasis airway (33) but is also increased in the sputum of patients with severe asthma (12), suggesting that it may be involved in the formation and development of bronchiectasis in patients with asthma.

Corticosteroids are potent drugs that suppress eosinophilic inflammation, and partially severe asthmatic patients may require oral corticosteroids to maintain stability (1). ICS play an established role in managing ACB (10). Consistently, our results showed that bronchiectasis severity was positively associated with increased inhaled corticosteroids use in the asthma-prior group. Notably, corticosteroids are potentially associated with the risk of PTB and pneumonia (34). As bronchiectasis induced by asthma presents prominent eosinophilic airway inflammation, patients may benefit even more from the type-2 targeted biologic therapy compared to the simple asthmatic patients.

Several studies have highlighted the therapeutic response of type-2 targeted biological therapy in severe asthmatic patients with bronchiectasis or NPs (35,36). Crimi et al. discovered that mepolizumab, an anti-interleukin (IL)-5 receptor, could effectively improve asthma symptom control and reduce annual exacerbations and corticosteroid intake in all patients with severe eosinophilic asthma, even in the subgroup with coexisting bronchiectasis (35). Similarly, a real-world multicenter study showed that benralizumab, an anti-IL-5 receptor α, can improve nasal outcome, asthma control, and lung function, and decrease eosinophilic inflammation in patients with severe eosinophilic asthma coexisting with NPs (36). Whether type-2 targeted biologic therapy can benefit patients with asthma-induced bronchiectasis in the early stages remains to be further explored. As suggested by the guidelines, bronchodilators may have an acceptable safety profile in bronchiectasis induced by asthma (10). Our project showed that the usage of bronchodilators increased with the development of bronchiectasis in the asthma-prior group. The airway clearance technique and pulmonary rehabilitation were recommended for partial bronchiectasis patients according to the guidelines (10,16); however, further research is needed to evaluate the latent benefits and risks for the asthma-induced bronchiectasis subgroup.

The current study indicated that the existence of bronchiectasis was related to previous PTB or pneumonia in childhood in the bronchiectasis-prior group. As against Western countries, childhood pneumonia caused by measles, pertussis, and PTB is the most commonly identified cause of acquired bronchiectasis in China (2). As against asthma-induced bronchiectasis patients, patients with bronchiectasis preceding asthma manifested a non-eosinophilic inflammation with lower FeNO, and the extent of bronchiectasis was positively associated with Pseudomonas aeruginosa isolated from the sputum. Previous studies have also shown that the eosinophilic inflammatory marker FeNO, which also reflects antimicrobial activity (37), is decreased in bronchiectasis, particularly when colonized by Pseudomonas aeruginosa (38). Moreover, the present study indicated that the existence and severity of bronchiectasis increased the frequency of pneumonia but did not affect the frequency of acute exacerbations of asthma in the bronchiectasis-prior group. The presence of bronchiectasis was more likely to be a combination than a factor promoting asthma to become more severe and exacerbated when the onset of bronchiectasis preceded asthma. Furthermore, the onset of bronchiectasis before asthma tends to be characterized by non-eosinophilic inflammation with recurrent pneumonia. This finding may be of great significance in guiding the precise treatment of asthma in the future.

As patients with the bronchiectasis-prior present with predominantly non-eosinophilic inflammation, increased corticosteroids usage may increase the risk of pneumonia without achieving symptomatic control. Guidelines for asthma suggested that type-2 targeted biologic therapy, such as anti-IgE, anti-IL-5, and anti-IL4R, should be recommended for stage 5 asthmatic patients with evidence of type 2 inflammation (1). One recent case series showed that treatment with biologics targeting type 2 inflammation leads to clinical improvement, including a reduction in corticosteroid courses, respiratory exacerbations, and systemic antibiotic courses in patients with asthma overlapping bronchiectasis (39). Our current findings suggest that there may be no additional benefit of using type-2 targeted biologic therapy for non-eosinophilic inflammation in bronchiectasis-prior patients. However, due to the potential infection risk of ICS, biologic therapy preceding ICS may benefit patients with type 2 inflammation in the bronchiectasis-prior group. Macrolides exert immunomodulatory effects on neutrophil-mediated lung damage suppression and enhancement of cilia function to promote mucociliary clearance. Guidelines for bronchiectasis recommend long-term treatment with macrolide antibiotics to reduce exacerbation in patients with recurrent exacerbations (11). Patients with neutrophil-predominant severe asthma tend to show a decline in exacerbation rate, improved peak expiratory flow, and improved quality of life when treated with macrolides (40). One retrospective study suggested that macrolides may be helpful as an add-on therapy in severe asthma-bronchiectasis overlapping patients (41). Owning to the non-eosinophilic inflammatory and recurrent pneumonia characteristics in the present study, bronchiectasis-prior patients may have benefited from macrolides therapy. Unfortunately, only three patients with bronchiectasis received long-term macrolide therapy in the present study, and further follow-up studies may provide more objective evidence.

It is well known that smoking history is a predisposing factor for COPD, but not asthma (1). The extent of bronchiectasis was correlated with a positive smoking history in the current study, consistent with previous findings (42). Particulates released by smoking might be involved in airway remodeling in patients with bronchiectasis-prior similar to COPD.

Comparably with asthma-induced bronchiectasis, the existence, severity, and BSI scores of bronchiectasis were associated with deteriorated lung function in the bronchiectasis-prior group. Regardless of etiology, clinicians and researchers should be aware of the presence of bronchiectasis in patients with asthma. Regular follow-up chest CT and lung function are necessary for the early detection and treatment of bronchiectasis in asthmatic patients. Meanwhile, the dose of the inhaled drug was positively correlated with the severity of bronchiectasis, regardless of the onset of bronchiectasis, indicating that the severity of bronchiectasis affected the step-treatment strategy by clinicians. Recent studies focused on the nutritional status and nutrient deficiency to the prognosis of bronchiectasis (43-45). As an indicator of nutritional status, BMI is a predictor of prognosis in bronchiectasis, and a lower BMI is linked to the severity and increased mortality in bronchiectasis patients (43,44). The present study presented that the severity of bronchiectasis was related to a lower BMI, regardless of the sequence of bronchiectasis onset in asthmatic patients. In summary, these results suggested that the severity of bronchiectasis was significantly associated with poor nutritional status and prognosis, and it should be closely monitored in asthmatic patients.

The British Thoracic Society guidelines recently recommended the BSI scoring system to predict further outcomes in bronchiectasis patients (10). Our results showed that BSI scores were positively related to Pseudomonas aeruginosa isolation and age and negatively correlated with FEV₁%predicted in the bronchiectasis-prior group, consistent with variables included in the BSI tool, indicating that the BSI tool is strongly predictive of the future outcomes in bronchiectasis preceding asthma patients (23). Notably, in the asthma-prior group, the BSI scores were positively related to the total IgE level and severe asthma exacerbation, suggesting that the coexistence of asthma acts as an adverse factor in bronchiectasis outcomes. Consistently, recent research indicated that the coexistence of asthma was an independent risk factor of bronchiectasis exacerbation (46). Whether the BSI tool is a perfect outcome predictor for asthma-induced bronchiectasis remains to be confirmed in the follow-up studies, and adding asthmatic factors to the BSI tool may be a better predictive system.

Limitations

This study has several limitations. First, there may be a selection bias because an assessment of the onset of bronchiectasis may be affected by the patients’ statement of history. Second, since the patients were enrolled at the respiratory and otorhinolaryngology departments, the rate of bronchiectasis in asthma could not reflect the epidemiological prevalence, although a correlation can be established. Longitudinal randomized controlled studies are necessary to determine the intrinsic causality and mechanisms of asthma and bronchiectasis. Third, we classified patients with “bronchiectasis diagnosed with HRCT coincident with the asthmatic symptoms” into the bronchiectasis-prior group, among which there were possibly a small number of asthma-induced bronchiectasis patients. Fourth, although the diagnosis of asthma in our study was strictly based on GINA guidelines, a small proportion of bronchiectasis patients with asthmatic components might be included. The differences and intrinsic correlations between bronchiectasis patients with asthmatic components and bronchiectasis combined with asthma in physiological and inflammatory characteristics, progression, treatment principles, and prognosis need further exploration.

Conclusions

The coexistence of asthma and bronchiectasis is a complex phenomenon. For patients with asthma, it is necessary to undergo follow-up chest CT and lung function to investigate bronchiectasis. The sequence of bronchiectasis onset may indicate distinct inflammatory characteristics. Meanwhile, detailed medical history collection is necessary to deliver targeted therapy for asthma comorbid with bronchiectasis.

Acknowledgments

We acknowledged Dr. Shuling Li and Dr. Qinghua Chen of the Department of Radiology of Beijing Tongren Hospital for the HRCT and paranasal sinus CT analysis.

Funding: This work was supported by Beijing National Science Foundation (No. 7212018), the Hospital Founding of Beijing Tongren Hospital (No. 2021-YJJ-PY-009), the National Natural Science Foundation of China (Nos. 81800014, 81970852, and 82171110), the Program for the Changjiang Scholars and Innovative Research Team (No. IRT13082), the Beijing Municipal Science and Technology Project (No. Z181100001618002) and the CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-022).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1288/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1288/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1288/coif). All authors report that this work was supported by Beijing National Science Foundation (No. 7212018), the Hospital Founding of Beijing Tongren Hospital (No. 2021-YJJ-PY-009), the National Natural Science Foundation of China (Nos. 81800014, 81970852, and 82171110), the Program for the Changjiang Scholars and Innovative Research Team (No. IRT13082), the Beijing Municipal Science and Technology Project (No. Z181100001618002) and the CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-022). The authors have no other conflicts of interest to declare.

Ethical Statement:The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee of the Beijing Tongren Hospital, Capital Medical University (approval No. TRECKY2019-070). Written informed consent was obtained from all enrolled patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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