Introduction
Bronchiectasis is a chronic suppurative lung disease characterized by permanent dilation of bronchi and bronchioles [
1]. The number of hospital admissions due to bronchiectasis are increasing [
2]. Pathophysiologically, the hypertrophy of mucus-secreting glands leads to excessive secretion of mucus into the airway. The normal clearance of the mucociliary system is compromised in patients with bronchiectasis, resulting in pooling of mucus within the airway [
3]. Excessive secretion and retention of mucus in the airway results in a chronic cough and continuous expectoration in patients with bronchiectasis. Inflammatory reactions, injury and distortion of bronchi, mucus retention, and respiratory infection or bacterial colonization are the four major components of the “vicious cycle” underlying the pathogenesis of bronchiectasis [
4,
5]. The population of patients with bronchiectasis is extremely heterogeneous. Aliberti et al. [
6] reported that “dry bronchiectasis” is an established clinical phenotype (27% of patients), and none of these patients had chronic infections or daily sputum production. The other three clusters of bronchiectasis were characterized by the presence of chronic infection with
Pseudomonas aeruginosa or other pathogens and daily sputum production [
6]. Mucus production plays an essential role in the other three clusters of bronchiectasis. It has been deduced that reducing the production of mucus or improving the clearance of sputum in the airway is the key to break down this “vicious cycle” and enhance the therapeutic efficacy for bronchiectasis.
Mucoactive drugs are commonly used to clear the airway in mucus hypersecretion diseases [
7]. Mucoactive agents, such as hypertonic saline, mannitol, and erdosteine, have greatly improved the treatment outcomes for bronchiectasis. It was found that a short-term regimen of erdosteine plus routine chest physiotherapy decreased mucus hypersecretion in stable patients with bronchiectasis [
8]. Another clinical trial showed that the inhalation of dry powder mannitol for 12 weeks significantly reduced the amount of sputum in bronchiectasis patients [
9]. Unfortunately, these trials were limited by their small sample sizes and short treatment period. A systematic review on the efficacy of mucolytics for bronchiectasis indicated that the level of evidence supporting the routine use of mucoactive agents for bronchiectasis was low [
10]. Therefore, large randomized controlled trials are needed to generate high level evidence on the efficacy of the long-term use of mucolytics for reducing the risk of exacerbations in patients with bronchiectasis.
Currently, investigators have found that N-acetylcysteine, an effective mucolytic agent, not only reduces the viscosity and elasticity of sputum, but it also has anti-inflammatory and antioxidant activity [
11,
12]. Moreover, N-acetylcysteine has shown a protective effect against the detrimental impact of lipopolysaccharide in vitro [
13]. In addition, a randomized, placebo-controlled trial with a large sample size demonstrated that a high dose of oral N-acetylcysteine (1200 mg/day) for 1 year significantly reduced the rate of exacerbations and improved the quality of life in patients with chronic obstructive pulmonary disease (COPD) [
14,
15]. Additionally, the Spanish guidelines on the treatment of bronchiectasis indicate that the use of N-acetylcysteine should be considered for patients with bronchiectasis and COPD [
16]. Furthermore, Oliveria et al. found that the oxidative stress biomarkers of adult bronchiectasis patients were significantly elevated in both cellular and plasma extracts [
17], suggesting that oxidative stress plays an important role in the pathophysiological changes of bronchiectasis. Therefore, as a classic mucolytic agent with antioxidant and anti-inflammatory properties, N-acetylcysteine can be effective in the treatment of bronchiectasis.
In this study, we aimed to assess whether the long-term use of oral N-acetylcysteine (600 mg, twice daily) might reduce the rate of exacerbations and improve the quality of life in patients with bronchiectasis.
Discussion
The results of this study showed that oral N-acetylcysteine treatment for 1 year in patients with bronchiectasis was associated with a reduction in the incidence of exacerbations compared with the control group in Shandong Province, China. In addition to the protective effect of N-acetylcysteine against exacerbations, this treatment at a dose of 600 mg twice daily had the advantages of reducing the volume of sputum and improving the quality of life of the bronchiectasis patients.
It is reported that the average frequency of exacerbations for bronchiectasis ranges from 1.5 to 6.5 per year [
5]. Frequent exacerbations have a negative impact on long-term clinical outcomes for bronchiectasis patients, including lung function deterioration, increased risk of hospitalization, and increased medical costs [
26,
27]. Therefore, there is an urgent need for clinical research dedicated to reducing the frequency of exacerbations. More recently, numerous studies have focused on the long-term use of macrolides for the treatment of bronchiectasis. Several major trials, including EMBRACE, BLESS, and BAT, consistently showed the efficiency of macrolides (azithromycin or erythromycin) in reducing the frequency of exacerbations in patients with bronchiectasis [
28‐
30]. However, the long-term use of macrolides increased the risk of bacterial resistance, with a high incidence of adverse events. More importantly, the rate of macrolide resistance and the incidence of gastrointestinal adverse effects in patients treated with azithromycin were 88 and 40%, respectively [
30]. Therefore, the safety profile of a treatment strategy should also be considered in the management of bronchiectasis.
Impairment of the mucociliary system in bronchiectasis patients is responsible for the excessive secretion of mucus and long-term retention of the sputum. Recently, increasing numbers of studies have focused on mucoactive agents. European Respiratory Society guidelines recommend offering long-term mucoactive treatment (≥3 months) in adult patients with bronchiectasis [
20]. However, RhDNase is not recommended by either the European Respiratory Society guidelines or the British Thoracic Society guidelines because there is evidence that rhDNase use is associated with worsening lung function in bronchiectasis [
5,
20]. The quality of life was found to be improved by the use of mannitol or hypertonic saline in a subgroup of patients with bronchiectasis [
9,
31]. Furthermore, Bilton et al. reported that the time to first exacerbation was prolonged in patients receiving mannitol as compared with the controls [
32]. However, few clinical research studies have reported the efficacy of mucolytic agents on the prevention of exacerbations in bronchiectasis patients. One reason might be the short-term therapy employed in previous trials, and another reason is that a certain subgroup of bronchiectasis patients might benefit more from mucoactive drugs. To the best of our knowledge, studies on the long-term use of N-acetylcysteine for the treatment of bronchiectasis have not been reported. In contrast to previous studies focusing on the use of other mucolytic agents in the treatment of bronchiectasis, the present study investigated N-acetylcysteine because it is not only an effective mucolytic agent but also has anti-inflammatory and antioxidant properties.
The role of N-acetylcysteine has been widely investigated in many studies involving patients with COPD. Both the PANTHEON and HIACE trials found that 1200 mg of N-acetylcysteine, daily, decreased the exacerbation frequency in Chinese patients with COPD [
15,
33]. Consistent with the COPD studies, our study found that the long-term use of oral N-acetylcysteine (600 mg, twice daily, 12 months) prevented exacerbations in patients with bronchiectasis in Shandong Province, China, accompanied by a decrease of the daily sputum volume and improvement in the quality of life. We supposed that the underlying mechanism of N-acetylcysteine in preventing exacerbations might be mediated via the reduced volume of sputum so that the “vicious cycle” was broken down. Furthermore, the anti-inflammatory and antioxidant properties of N-acetylcysteine were also responsible for the results. In addition, evidence from in vitro studies indicates that N-acetylcysteine has the ability to interfere with biofilm formation and disrupt biofilms so that the survivability of bacteria in the respiratory tract can be inhibited [
34].
Although our results indicated that the time to the first exacerbation did not differ between the N-acetylcysteine group and the control group, significantly more patients remained exacerbation-free in the N-acetylcysteine group than in the control group. Furthermore, the time to the second exacerbation was longer in the N-acetylcysteine group than in the control group. Our findings are consistent with those of the long-term PANTHEON study [
15]. The positive cultures for
P. aeruginosa were not different between the two groups. To investigate the difference of positive cultures, patients need to be stratified according to the results of the baseline bacterial culture. Patients with chronic colonization of
P. aeruginosa are more likely to benefit from the treatment. In addition, no improvement in pulmonary function was observed after N-acetylcysteine treatment for 1 year, which is consistent with the results of the PANTHEON and HIACE trials [
15,
33]. Probably, reducing the frequency of exacerbations and improving the quality of life of the patients have nothing to do with the bronchodilation effect.
Similar to other clinical studies regarding the long-term use of N-acetylcysteine, our study found that long-term N-acetylcysteine therapy was safe. A low incidence of adverse reactions was reported in patients with bronchiectasis, indicating that N-acetylcysteine was well tolerated. In addition, it has been reported that N-acetylcysteine-related adverse drug reactions are mainly associated with anaphylactoid reactions to N-acetylcysteine [
35]. Anaphylactoid reactions are nonimmunogenic and do not require prior sensitization. The precise mechanisms of these reactions remain unclear, although non-mast cell sources of histamine are likely to play a role [
36]. Body odor and gastrointestinal adverse reactions were found in our study, but they did not affect the overall efficacy of N-acetylcysteine. Of note, the use of N-acetylcysteine can avoid the problems of gastrointestinal adverse reactions and bacterial drug resistance caused by long-term azithromycin therapy [
30].
To the best of our knowledge, this BENE study was the first trial to explore the efficacy and safety of long-term use of N-acetylcysteine for the treatment of bronchiectasis in China. However, this study had several limitations. First, the subjects were enrolled from the same province in China, reflecting a rather homogenous population of bronchiectasis patients. There is some geographical variation in etiology, epidemiology, and microbiology of bronchiectasis [
37]. Besides, inconsistent diagnostic criteria were used to study the etiology of bronchiectasis. As a result, the proportion of idiopathic bronchiectasis patients in the Chinese population [
18,
38] seems to be higher than that in the Spanish registry, which reported that only 24% were idiopathic [
39]. The prognosis and management of bronchiectasis might differ between various geographic regions. Therefore, the effect of N-acetylcysteine on a Chinese population might differ from that in other populations. Along with the small sample size, these factors may influence the results. Hence, larger trials of heterogenous populations of bronchiectasis patients are needed to validate our results. Second, this study did not compare N-acetylcysteine to a placebo. Thus, there is a concern for bias. For example, N-acetylcysteine might also have been used in the control group. In addition, both researchers and patients were not blinded to the interventions, which may introduce the placebo effect. Due to these methodological flaws, the recommendation of long-term use of N-acetylcysteine in bronchiectasis cannot be made until the current results are validated in larger international multicenter trials. Third, this study did not analyze the therapeutic effects of N-acetylcysteine separately for “dry bronchiectasis,” “daily sputum,” or other subtypes of bronchiectasis. Since sputum production and chronic infection were less frequent in the “dry bronchiectasis” cluster, it is unclear whether the “dry bronchiectasis” group would benefit from the long-term use of N-acetylcysteine. Subgroup analysis of bronchiectasis according to microbiology and daily sputum suggests that different clinical phenotypes of bronchiectasis might exhibit diverse treatment outcomes in the same trial [
6]. Different clinical phenotypes may require different treatments. Further studies are needed to explore how they are affected by treatment. Finally, nebulized N-acetylcysteine might be an effective way to deliver the drug, in contrast to oral administration, which involves first-pass liver metabolism and may result in a decreased efficacy or an increased toxicity. Further studies are needed to explore the efficacy and safety of nebulized N-acetylcysteine for bronchiectasis patients.
In conclusion, the long-term use of N-acetylcysteine is able to reduce the risk of exacerbations for bronchiectasis patients in Shandong Province, China. This trial may lead to larger international multicenter research in the field.