Abstract
Macrolides, mucoactive drugs and adherence are crucial for the management of bronchiectasis http://ow.ly/H4oq30fZArC
To the Editor:
The publication of the first European Respiratory Society guidelines for management of bronchiectasis [1] is a landmark of recent advancement in the field. Whilst the British Thoracic Society guidelines [2] delineated mechanisms of pathogenesis and offered recommendations for management of bronchiectasis, the latest document specifically addressed nine clinically important questions that may better inform clinical decisions. Although it is likely that these recommendations can be extrapolated to patients in Asian countries such as China, we have some further suggestions and/or recommendations for refinement.
First, the optimal length of macrolide administration should be clarified. No clear definition of long-term administration (e.g. 6, 12 or 24 months) was stated in the guidelines. Although gastrointestinal tract (e.g. nausea and diarrhoea), cardiac (e.g. prolonged QT intervals) and hearing disorders have been reported, most adverse events were mild, and can be readily identified and managed. The major issue concerning long-term use of macrolides lies within clinical benefit. Despite convincing positive outcomes (significantly reduced exacerbation frequency and improved quality of life) [3], the observational duration in most clinical trials [4–6] was <2 years. Notably, prolonged use of macrolides has been associated with changes in sputum microbial compositions (determined with 16S ribosomal RNA sequencing) and an increased risk of harbouring macrolide-tolerant Pseudomonas aeruginosa [7]. Furthermore, long-term use of macrolides did not reduce exacerbation frequency among patients from whom P. aeruginosa was not isolated [7], questioning the validity of long-term prescription in bronchiectasis. Whilst long-term macrolides should be prescribed to patients in whom oral antibiotics are contraindicated, no clinical trials to date have directly addressed the long-term benefits of macrolides for bronchiectasis patients with and without P. aeruginosa colonisation. It remains unclear whether prolonged use of macrolides (e.g. >2 years) could reduce the risks of bronchiectasis exacerbations. How long should the optimal duration be for macrolides prescription needs to be addressed. Caution should be exercised when interpreting findings from existing clinical trials.
Second, indications for use of mucoactive drugs should be better defined. Airway clearance, including upper airway clearance (e.g. nasal irrigation for patients with chronic rhinosinusitis), and facilitation of sputum expectoration are cardinal management recommendations for bronchiectasis. No existing trials have confirmed the superiority of airway clearance and mucoactive drugs. Physicians are concerned about which subpopulation might benefit more from mucoactive drugs. The recommendation to prescribe mucoactive drugs in patients who have difficulty in expectoration despite maintenance airway clearance was primarily based on mixed findings from clinical trials, which had limited sample sizes and durations. Whereas effects of inhaled mannitol on clearing sputum and prolonging the time to exacerbations were convincing, no trials have investigated whether other mucoactive drugs (high-dose N-acetylcysteine, carbocisteine and ambroxol) provide clinical benefits in bronchiectasis. Apart from mucolytic effects, mucoactive drugs (particularly at higher doses) confer anti-inflammatory and antioxidative stress effects that clinically translate into reduced exacerbation frequency (particularly repetitive exacerbations), longer time to exacerbation and improved quality of life in chronic obstructive pulmonary disease [8, 9]. Therefore, higher doses of mucoactive drugs might confer similar clinical benefits in bronchiectasis. Furthermore, the optimal duration of mucoactive drug administration needs to be determined. The current guidelines mostly focused on inhaled mucoactive drugs; however, whether oral mucoactive drugs elicit fewer side-effects and achieve better outcomes remains an open question. In light of the fact that airway clearance alone might not be sufficient for maintenance therapy and that self-administered airway clearance has not been regularly performed by bronchiectasis patients, we suggest that mucoactive drugs be used regardless of whether airway clearance is applied.
Finally, the importance of adherence to maintenance treatment has not been properly addressed. According to findings from our patients' interview, only ∼40% of patients were adherent to maintenance therapy, defined as continuous use of at least one category of medication and/or airway clearance technique (unpublished data). Patients who were adherent to therapy commented that withdrawal of medications would readily lead to progressive worsening of respiratory symptoms, whereas patients who were not adherent to maintenance therapy asserted that treatment resulted in very limited clinical benefits, that they already have “got used to daily coughing and sputum expectoration” and that prolonged use of medications might lead to “irreversible adverse effects” (e.g. frailty, infertility and gastrointestinal/renal disorders). This echoed the findings of McCullough et al. [10], who demonstrated that beliefs about treatment, perceived treatment burden, the number of prescribed medications and age were predictors of adherence. Despite limited evidence supporting the benefits of long-term therapy, we did notice that nonadherence or complete withdrawal of medication might predispose to poor clinical outcomes, such as radiological progression and/or worsening of respiratory symptoms. More studies are warranted to determine the consequences of medication withdrawal (e.g. clinical deterioration), particularly following a longer period of time. Results from these studies would shed light on the critical roles of maintenance therapy in bronchiectasis. Refinement of guidelines (incorporating recommendations to strengthen patient education) may achieve better outcomes.
Disclosures
Supplementary Material
R-c. Chen ERJ-01987-2017_Chen
W-j. Guan ERJ-01987-2017_Guan
N-s. Zhong ERJ-01987-2017_Zhong
Acknowledgements
W-J. Guan, Y. Huang and C-L. Chen drafted the manuscript; R-C. Chen and N-S. Zhang critically reviewed the manuscript and approved final submission.
Footnotes
Support statement: This work was supported by National Natural Science Foundation grant number 81400010, Pearl River S&T Nova Program of Guangzhou grant number 201710010097, Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme 2017 (to W-J. Guan), Changjiang Scholars and Innovative Research Team in University grant ITR0961, The National Key Technology R&D Program of the 12th National Five-year Development Plan grant 2012BAI05B01 and National Key Scientific & Technology Support Program “Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer” grant number 2013BAI09B09 (to N-S. Zhong and R-C. Chen). Funding information for this article has been deposited with the Crossref Funder Registry.
Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com
- Received September 28, 2017.
- Accepted September 30, 2017.
- Copyright ©ERS 2018