Pseudomonas aeruginosa isolation is an important predictor for recurrent hemoptysis after bronchial artery embolization in patients with idiopathic bronchiectasis: a multicenter cohort study

Bronchiectasis, a permanent and progressive bronchial deformation due to fibrosis of the bronchial wall muscles and destruction of elastic tissue, presents with chronic cough, purulent sputum, and recurrent hemoptysis [1, 2]. Aetiologies include congenital, idiopathic, post-infection, immunodeficiency, chronic obstructive pulmonary disease, connective tissue disease, ciliary dysfunction, and allergic bronchopulmonary aspergillosis [2, 3], with idiopathic bronchiectasis the most common in China [4, 5].

The United States Bronchiectasis Research Registry reported that 23% of patients with bronchiectasis had a history of hemoptysis [1]. The hemoptysis volume was larger than other diseases with more cases leading to recurrence [6]. In-hospital death rates due to hemoptysis among adults with bronchiectasis occurred in approximately 4.5–9.2% of hospitalizations [7, 8]. Bleeding arteries of patients with idiopathic bronchiectasis included bronchial arteries (BAs) and non-bronchial systemic arteries (NBSAs) [9]. BAs are systemic arteries running through the hilum around the main bronchus that enter the lung, including BAs directly from the descending thoracic aorta, and aberrant BAs (AbBAs) from outside this area [10].

Bronchial arterial embolization (BAE) has become the first-line treatment for hemoptysis [11]. However, nearly one-third of patients experience recurrent hemoptysis one year after BAE, and one-fifth of patients after BAE still require repeated embolization [12, 13]. A few clinical studies suggest that recurrent severe hemoptysis after BAE was associated with hemoptysis history, age, bronchial-pulmonary shunt, and NBSAs [2, 12]. However, these studies have overlooked other clinical indicators including pathogenic microorganisms and computed tomography (CT) imaging. In addition, few studies have specifically investigated the risk factors associated with recurrent hemoptysis with idiopathic bronchiectasis.

Therefore, this multicenter retrospective cohort study aimed to report the prevalence of the recurrence of hemoptysis in patients with idiopathic bronchiectasis who received BAE. Furthermore, we aimed to identify the independent risk factors of recurrence comprehensively including medical histories, pathogens, CT imaging, and responsible arteries.

In this multicenter retrospective cohort study, the presence of recurrent hemoptysis was high in patients with idiopathic bronchiectasis after BAE affecting almost half of patients, while one-quarter of patients needed a second BAE or lobectomy. Recurrent hemoptysis correlated with P. aeruginosa infection, massive sputum production, abnormal AbBAs, and extensive bronchiectasis. Furthermore, recurrent severe hemoptysis was associated with P. aeruginosa infection, abnormal AbBAs, and age.

Several studies have investigated the recurrence of severe hemoptysis among different aetiologies of bronchiectasis. All 588 patients in this study were idiopathic bronchiectasis patients, and this is the first study to our knowledge assessing a single aetiology on BAE and hemoptysis recurrence. The cumulative recurrent severe hemoptysis rates in this study were similar to previous studies [12, 13, 18]. The recurrence rate of hemoptysis in patients with bronchiectasis was lower than in patients with mycobacterium, fungal infection, or a post-tuberculous phenotype of bronchiectasis [20, 21]. A previous retrospective study of 106 bronchiectasis patients revealed that neither the bacteria, presence of NBSAs, nor the number of bronchiectatic lobes correlated with hemoptysis control [18]. Notably, this previous study [18] did not focus on P. aeruginosa, and the number of bronchiectatic lobes was less than that in our study. Another study showed lung destruction, sex, and systemic arterial-pulmonary circulation shunts could be used to predict recurrence [13]. Instead of lung destruction, this study classified and described the CT findings of patients in detail [22].

Patients with P. aeruginosa had more severe radiological findings, worse lung function, and more stubborn disease [23‐25]. P. aeruginosa, as a risk factor for exacerbated bronchiectasis [26], has attracted attention in bronchiectasis because of its high drug resistance, easy colonization, and repeated exacerbation [27‐29]. Multiple mutations exist in the genotype of P. aeruginosa isolated from patients with bronchiectasis [27]. We have reported that virulence genes exoU or pldA of P. aeruginosa led to a higher incidence of exacerbation in patients with idiopathic bronchiectasis [30]. A vicious cycle of inflammation and infection can perpetuate symptoms and further airway damage. Guidelines recommend that patients with first isolation P. aeruginosa should be treated with eradication antibiotics [31], while long-term inhaled antibiotic or oral macrolides are recommended for patients with three or more repeated exacerbations per year [14, 32]. Whether long-term antimicrobial prophylaxis (such as macrolide) can reduce the risk of recurrent hemoptysis needs to be confirmed in prospective studies. Furthermore, this study showed that severe recurrent hemoptysis in patients with isolated P. aeruginosa was 2.87 times higher than that in patients without P. aeruginosa. Bronchiectasis patients with hemoptysis may be treated with antibiotics guided by routine sputum examination and antibiotic susceptibility results. More prospective or even randomized controlled trials are needed to explore management strategies for patients with bronchiectasis with P. aeruginosa infection to further optimize treatment guidelines.

Considering that patients with P. aeruginosa infection manifested more purulent sputum [33], this study specifically excluded the possibility of collinearity between P. aeruginosa and 24-h sputum volume so that sputum volume was an independent predictor of recurrent hemoptysis. Although recommended for bronchiectasis [14], airway clearance techniques might aggravate hemoptysis. Therefore, it is necessary to select appropriate airway clearance techniques or use expectorants regularly to discharge sputum.

In general, the severity of bronchiectasis should be associated with a recurrence incidence of hemoptysis. Therefore, we evaluated the severity of bronchiectasis with the bronchoarterial ratio, the number of bronchiectatic lobes, and bronchiectatic type on CT scans, and explored the correlation of bronchiectasis severity with recurrence. The multiple Cox regression analysis showed that recurrent hemoptysis was positively correlated with the number of bronchiectatic lobes. A Korean study showed that the number of bronchiectatic lobes was positively related to the in‑hospital mortality, and negatively related to the survival rate [34]. Efforts should be made to delay the progression of bronchiectatic lobes, especially in patients with hemoptysis.

Abnormal arteries manifested as dilatation, exudation, vasoganglion formation, aneurysms, and arterial-pulmonary circulation shunts on CTA or digital subtraction angiography. Proper esophageal arteries accounted for 17.7% (n = 183) of NBSAs in this study. We have reported that proper esophageal arteries can be involved in hemoptysis, especially when the basal segment of the lobe is involved [35], which was confirmed in South Korea [36]. The pulmonary plexus originates from the dorsal aorta during embryonic development. Once connected to the pulmonary arteries, the primitive BAs begin to degenerate, which results in only some branches formed in adults [37]. The proportion of AbBAs originating from the subclavian and its branches were the largest, indicating more persistence of primitive branches of high origin [38]. According to embryonic development, AbBAs are also probably potential in the general population; however, these arteries are too thin to be discerned on CTA. Chronic infection may induce vascular thickening, making them easier to identify. Compared to patients without abnormal AbBAs on CTA, patients with abnormal AbBAs had an increased incidence of recurrent severe hemoptysis in this study, supporting the idea that the pulmonary vascular system developed before the tracheal system and the development of BAs was due to some stimulus [37]. As the lung developed, some blood vessels degenerated, but arteries of incomplete degeneration may thicken during infection. Therefore, more attention should be paid to abnormal AbBAs.

One strength of our study is that this was a multicenter study with the largest cohort of patients with idiopathic bronchiectasis. Endovascular treatments of hemoptysis were performed in more than 1000 cases per year in our hospital, and the operators of BAE in the eight centers were trained uniformly, which provided reassurance for this research. The second strength is that specific abnormal arteries were identified. The Third strength is that this study indicated the significance of P. aeruginosa in the recurrence of hemoptysis and suggested the importance of P. aeruginosa clearance therapy.

This study has some limitations as well. First, there is recall bias and reporting bias. Second, some unspecified and unquantifiable factors, such as environmental exposures, climatic variation, lifestyle, and psychosocial factors, also affect the outcomes of bronchiectasis [39] and require a more thorough investigation. We hope to improve these data in the future by conducting a prospective trial.

In summary, factors associated with relapse of hemoptysis after BAE in patients with idiopathic bronchiectasis are P. aeruginosa infection, massive sputum production, abnormal AbBAs, and extensive bronchiectasis. Recurrent severe hemoptysis correlated with age, P. aeruginosa infection, and abnormal AbBAs. In view of we could not change the responsible vascular malformation and the degree of bronchiectasis. Therefore, the isolation of P. aeruginosa from patients requires further attention, and the appropriate airway clearance techniques should be individually applied after BAE.