1. Introduction
Chronic airway infection, inflammation and destruction are principal components of the vicious cycle [Citation1] which is implicated in the pathogenesis of non-cystic fibrosis bronchiectasis (termed bronchiectasis hereafter), a debilitating disease with progressively increasing morbidity and mortality [Citation2,Citation3]. Despite raising global awareness that bronchiectasis is not an orphan lung disease, current management has been hampered by the limited medications that effectively break the vicious cycle. Despite this, current therapies for bronchiectasis target at reducing symptoms, improving quality-of-life, preventing exacerbations, preserving lung function and sustaining longevity. The substantial disease burden, coupled with urgent clinical needs, has fueled renewed research interests in exploitation and development of inhaled medications for bronchiectasis. Currently, some inhaled medications have been endorsed by the latest international guidelines [Citation4,Citation5]. Compared with oral and intravenous administration, inhaled therapy may achieve high drug concentrations within lower airways while minimizing systemic adverse effects. Nonetheless, a significant gap remains between current knowledge and the expectation of future clinical practice.
Whilst we will briefly review the status quo and highlight future prospects of inhaled therapy for bronchiectasis, further details could be referred to in the latest review [Citation6]. summarizes the main characteristics of previous and current clinical trials involving different categories of inhaled medications in bronchiectasis. delineates the potential mechanisms of action for individual category of inhaled medications.
Table 1. Summary of clinical trials involving different categories of inhaled medications in bronchiectasis.
Figure 1. Potential mechanisms of action of individual category of inhaled medications.
Recurrent airway infection, chronic inflammation and airway destruction are the three main components of the vicious cycle in patients with bronchiectasis. Major pathological changes of the bronchiectatic airways include mucus hypersecretion and/or plugging, bacterial colonization (including biofilm formation), mucociliary dysfunction, smooth muscle hyperplasia and inflammatory cell infiltration. Therefore, pharmacological interventions which target at multiple pathways may be applicable to the management of bronchiectasis. Expectorants act on the mucus lining the airway surface, increasing the osmotic pressure to facilitate mucus hydration and expectoration. Antibiotics may reduce the airway bacterial load or help eradicate pathogenic bacteria such as Pseudomonas aeruginosa, thereby suppressing airway inflammation. Bronchodilators plus inhaled corticosteroids may have synergistic effects on suppressing airway inflammation. Oxidative stress also plays a role in orchestrating the vicious cycle, which might be alleviated by inhaled hydrogen therapy. Other anti-inflammatory medications (e.g. anti-neutrophil) are also under development.
2. Inhaled therapy for bronchiectasis: a historical view
Inhaled antibiotics for treatment of lung abscess and bronchiectasis was initially proposed by Hewitt in 1952 [Citation7]. Since then, inhaled therapy with different regimens (e.g. tobramycin, hypertonic saline) has been sparsely prescribed in patients with bronchiectasis. The use of inhaled therapy was accelerated since the last two decades, when the efficacy of inhaled corticosteroids and/or long-acting beta-agonists (e.g. budesonide/formoterol, fluticasone/salmeterol) and muscarinic receptor antagonists (e.g. tiotropium) were tested in clinical trials of bronchiectasis. The list of medications quickly expanded to other categories, including antibiotics (e.g. tobramycin, gentamicin, aztreonam, ciprofloxacin, amikacin, colistimethate), mucolytics (e.g. recombinant human RNase, N-acetylcysteine), expectorants (e.g. mannitol, hypertonic saline), and anti-neutrophil medications (e.g. CHF63339).
Most trials investigating the effects of expectorants were initiated early but few are ongoing. Similarly, clinical trials of inhaled corticosteroids and/or long-acting beta-agonists were performed early, but a trend toward efficacy assessment of a broader spectrum of anti-inflammatory medications (e.g. muscarinic receptor antagonists, anti-neutrophil medications) was noted. The list of clinical trials investigating inhaled antibiotics follows on from the success of these agents in the cystic fibrosis population ().
Despite different mechanisms underlying disease pathogenesis, therapeutic principles of bronchiectasis have been largely derived from other respiratory diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Nevertheless, some therapeutic principles cannot be directly extrapolated to bronchiectasis. Inhalation of recombinant human DNase, a medication which was reportedly effective in cystic fibrosis, was associated with more frequent exacerbations and rapid decline in lung function in idiopathic bronchiectasis [Citation8]. Therefore, caution should be exercised for interpretation of findings in different chronic respiratory diseases.
3. Status quo of inhaled therapy for bronchiectasis
In view that bronchiectasis is characterized by recurrent airway infection and inflammation, priority has been given to the development of inhaled antibiotics. Apart from gentamicin solution (phase IV), the efficacy and safety of most antibiotics have been assessed in phase 2 (amikacin solution, tobramycin dry powder, liposomal ciprofloxacin) and phase III (dual-release ciprofloxacin, ciprofloxacin dry powder, tobramycin solution, colistimethate sodium solution) clinical trials. Efforts have been made in the refinement of formula (e.g. from solution to dry powder or dual-release powder), which is expected to result in higher levels of deposition or increased levels in airway epithelial lining fluid.
Apart from hypertonic saline nebulization, the inhalation of mannitol dry powder has offered a more patient-friendly approach for daily administration. Inhalation of mannitol is independent on the use of nebulizers and requires a shorter duration of administration. However, exploration of mucolytics, such as N-acetylcysteine and ambroxol, has not proceeded into clinical trials in bronchiectasis.
Inhaled corticosteroids, long-acting beta-agonists and muscarinic receptor antagonists are the commercialized medications that have gained extensive clinical application in other chronic respiratory diseases. Although these medications have been prescribed to patients with bronchiectasis, no large-scale clinical trials have been undertaken to characterize the responders and nonresponders.
4. How could bronchiectasis patients benefit from inhaled therapy?
Antibiotics remain the most potent medication for eradicating bacteria, thus alleviating airway inflammation. Short- and long-course inhaled or intravenous antibiotics administration was associated with ameliorated airway and systemic inflammation in bronchiectasis [Citation9]. Most inhaled antibiotics reduce sputum bacterial load and improve the quality of life, but this did not consistently translate into clinical benefits and might increase the risks of drug resistance [Citation10]. For use of some antibiotics (e.g. aztreonam), bronchospasm has been noted in some bronchiectasis patients, which could have constrained further use of inhaled antibiotics in a subgroup of patients. Nonetheless, bronchospasm is generally transient and mild-to-moderate in severity, therefore antibiotics could still be administered provided that proper monitoring was implemented.
An important paradigm for bronchiectasis management has been proper airway drainage and ease of sputum expectoration. Inhaled mannitol has been associated with prolonging the time to the first acute exacerbation after its introduction, and improving the quality of life, whereas hypertonic saline nebulization reduced bacterial burden and improved quality of life, but interestingly had no impact upon exacerbation frequency requiring antibiotics [Citation11].
The effects of inhaled anti-inflammatory medications have been less clear in bronchiectasis. Despite that inhaled corticosteroids plus long-acting beta-agonists might be associated with ameliorated dyspnea and more cough-free days [Citation12], inhaled corticosteroids alone or in combination with long-acting beta-agonists are not recommended for patients with concomitant asthma and/or airway hyperresponsiveness, and Pseudomonas aeruginosa colonization, according to the latest European Respiratory Society guidelines [Citation5].
5. What are the uncertainties?
Although clinical benefits of antibiotics inhalation are remarkable, prolonged use is linked to greater likelihood of drug resistance. The reduction in sputum bacterial load was typically more prominent during the first dosing period, but subsequently tapered upon repetitive dosing. To minimize resistance, intermittent administration (typically, on-off cycles) is recommended. It remains unclear whether inhaled antibiotics should be administered on a long-term basis (e.g. at least two consecutive years), and whether rotated use would minimize the risks of antibiotic resistance.
Whilst repeated antibiotics administration predisposes to resistance acquisition, inhaled expectorants/mucolytics may be an appealing maintenance therapeutic option. However, due to the lack of head-to-head comparisons, non-inferiority of inhaled expectorants compared with inhaled antibiotics has not been verified. Moreover, whether mucolytics (e.g. N-acetylcysteine) are equally effective compared with expectorants (i.e. mannitol) needs to be tested in future clinical trials.
Bronchiectasis is a chronic airway disease characterized by mucus hypersecretion; therefore, inhaled medication would also have to contend with mucus in the airway that impairs drug delivery. How mucus clearance improves the efficacy of inhaled medications is an interesting area of research.
Finally, the roles of anti-inflammatory medications have not been systematically investigated. If the additive effects to antibiotics and/or expectorants could be proven, priority should also be given to anti-inflammatory medications because the need for de novo drug development is absent.
6. Expert opinion
6.1. The next frontier
6.1.1. Refinement of the formula and inhaler devices
The goal of refining the medication formula (e.g. liposomal or dual-release ciprofloxacin) is to achieve better absorption, thus leading to greater post-dosing concentrations within airways. Properly designed inhaler devices should be tailored to patient’s needs so that those with significantly impaired inspiratory muscle strength, severe lung function impairment or poor mastery of inhalation techniques could still benefit from inhaled therapy, particularly dry powder inhalation through actuation. Compared with twice or thrice daily administration, once-daily inhalation may be a more attractive dosing scheme for most patients who have suboptimal adherence.
6.1.2. Development of novel medications and combinations
Because of the pleiotropic nature of airway inflammation, other medications (e.g. follistatin, molgramostim, macrolides, neutrophil elastase inhibitor, low-dose nitric oxide, neutrophil-targeted monoclonal antibodies) might have a role for management of bronchiectasis through different pathways. Notably, it was not until recently when anti-oxidative effects of hydrogen inhalation have been verified [Citation13]. Whether hydrogen inhalation could effectively reduce exacerbation frequency and ameliorate airway oxidative stress remains an interesting research question (NCT02765295). Further research is needed to test the superiority of medication combinations (e.g. corticosteroids plus neutrophil elastase inhibitors) versus single regimen. Addressing which antibiotic(s) or combinations are most effective for eradication of potentially pathogenic microorganisms (e.g. Pseudomonas aeruginosa) is necessary [Citation14].
6.1.3. Identifying the optimal patient population
Not all patients are candidates for prescription of inhaled therapy. Patients should be closely monitored to identify possible adverse events. Bronchospasm remains the most common adverse event that has restricted further application in patients with documented airway hyperresponsiveness, allergic bronchopulmonary aspergillosis and/or asthma. Patients with preserved lung function and younger patients are suitable for inhalation of dry powder via portable devices, whereas nebulization via ultrasonic devices may be achieved among those with significantly impaired lung function. Patients with more severe bronchiectasis might be better candidates for inhaled therapy (e.g. regular domiciliary antibiotics administration). This justifies the need to thoroughly phenotype bronchiectasis patients according to their clinical characteristics. However, it remains to be determined whether inhaled antibiotics for maintenance therapy are suitable for patients with purulent culture-negative sputum production. Properly defining the primary end point may help identify responders through pragmatic clinical trials.
6.1.4. Recommendations for developing countries
Many developing countries are still facing with practical issues of limited available medications, particularly the management of patients residing in the vast rural areas. Cost-effectiveness may have become a major determinant for prescription in these clinical settings. Therefore, priority should be given to clinically available medications that are suitable for maintenance therapy. Aminoglycosides (the currently recommended antibiotics, such as tobramycin), hyperosmotic expectorants (e.g. hypertonic saline) and short-acting bronchodilators (e.g. salbutamol, ipratropium) could be prioritized for community-based application.
Declaration of interest
WJ Guan declares that he has received National Natural Science Foundation No. 81,400,010, Pearl River S&T Nova Program of Guangzhou No. 201,710,010,097, and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme 2017. YH Gao declares that he has received National Natural Science Foundation No. 81,500,006. N Zhong and RC Chen declare that they have received Changjiang Scholars and Innovative Research Team in University ITR0961, The National Key Technology R&D Program of the 12th National Five-year Development Plan 2012BAI05B01 and National Key Scientific & Technology Support Program: Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer No. 2013BAI09B09. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
One peer reviewer on this manuscript has declared that they are co-PI on two clinical trials for inhaled therapies for bronchiectasis (CLEAN-PCD study through Parion/Vertex and the Willow Study through INSMED), as well as a possible PI for the PROMIS II through Chiltern/Zambon.
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References
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