Management of airway mucus hypersecretion in chronic airway inflammatory disease: Chinese expert consensus (English edition)



# Introduction
Airway mucus hypersecretion is an important pathophysiological and clinical manifestation of chronic obstructive pulmonary disease (COPD), bronchial asthma (asthma), bronchiectasis, pulmonary cystic fibrosis, and other chronic airway inflammatory diseases. [bib_ref] Airway mucus function and dysfunction, Fahy [/bib_ref] Recent studies have shown that inflammation and oxidative stress are involved in the pathogenesis of chronic airway inflammatory diseases and closely correlate with clinical outcomes and that they trigger excessive mucus production and secretion by glands and goblet cells. The American Thoracic Society, European Respiratory Society, and Chinese Thoracic Society of the Chinese Medical Association have officially recognized that airway mucus hypersecretion plays an important role in common respiratory diseases. [bib_ref] Advances in mucous cell metaplasia: a plug for mucus as a therapeutic..., Curran [/bib_ref] [bib_ref] Revisited role for mucus hypersecretion in the pathogenesis of COPD, Cerveri [/bib_ref] Reducing the risk of mortality and other complications associated with airway mucus hypersecretion means exploring its pathogenesis in detail, as well as clarifying its relationship with chronic airway inflammatory diseases. [bib_ref] Airway mucus function and dysfunction, Fahy [/bib_ref] [bib_ref] Advances in mucous cell metaplasia: a plug for mucus as a therapeutic..., Curran [/bib_ref] [bib_ref] Revisited role for mucus hypersecretion in the pathogenesis of COPD, Cerveri [/bib_ref] To take stock of available evidence and to guide both clinical practice and research initiatives, the COPD Group and Asthma Group of the Chinese Thoracic Society of the Chinese Medical Association have developed this consensus statement about the state of knowledge and best clinical practices for managing airway mucus hypersecretion induced by chronic airway inflammatory disease.

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Shen et al from submucosal glands. [bib_ref] Airway mucus function and dysfunction, Fahy [/bib_ref] [bib_ref] Advances in mucous cell metaplasia: a plug for mucus as a therapeutic..., Curran [/bib_ref] Under normal conditions, mucus secreted into the airway protects the airway and moistens the air. Under many types of stress conditions, including smoking, infection, pathogenic factors, and oxidative stress, cells lining the airway secrete numerous prosecretory factors that lead to secretory cell hypertrophy and goblet cell hyperplasia in the airway, with concomitant overproduction of mucus. [bib_ref] Airway mucus function and dysfunction, Fahy [/bib_ref] COPD, asthma, and bronchiectasis involve airway mucus hypersecretion and ciliary dysfunction. In COPD, inflammatory responses induced by cigarette smoke and other stimulators, together with oxidative stress, injure airway epithelial cells and stimulate mucus hypersecretion. In bronchial asthma, oversecretion of mucin components MUC5AC and MUC5B in the airway, and damage to the epithelium, cause the exfoliation of ciliated cells, goblet cell hyperplasia, and submucosal gland hypertrophy, all of which ultimately lead to airway mucus hypersecretion. [bib_ref] Mucoactive agents for airway mucus hypersecretory diseases, Rogers [/bib_ref] In bronchiectasis, irreversible expansion of the bronchial lumen compromises mucus clearance and allows bacteria to colonize the airway. The release of toxins secreted by bacteria first causes the activation of pathogen-associated molecular patterns and danger-associated molecular patterns to increase inflammation; this inflammation in turn stimulates goblet cell hyperplasia and metaplasia, leading to airway mucus hypersecretion. [bib_ref] Dampening inflammation, Henson [/bib_ref] [bib_ref] SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway..., Korfhagen [/bib_ref] [bib_ref] The role of airway epithelial cells and innate immune cells in chronic..., Holtzman [/bib_ref] [bib_ref] Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation..., Tyner [/bib_ref] Various types of stimulation, such as cigarette smoking, induce abundant production of reactive oxygen species and proteases, which activate epidermal growth factor receptor, Toll receptor, and other receptors, in turn triggering multiple signaling pathways such as MAPK, ERK, and NF-B. These pathways induce goblet cell metaplasia and hyperplasia in the airway, leading to synthesis and secretion of excessive mucin and thus to airway mucus hypersecretion. [bib_ref] Advances in mucous cell metaplasia: a plug for mucus as a therapeutic..., Curran [/bib_ref] [bib_ref] Revisited role for mucus hypersecretion in the pathogenesis of COPD, Cerveri [/bib_ref] In this way, inflammation, oxidative stress, protease imbalances, cholinergic nerve dysfunction, and other pathophysiological mechanisms can influence the risk of airway mucus hypersecretion. In addition to environmental stimulants, genetic susceptibility factors can also influence such risk. [bib_ref] Dissecting the genetics of chronic mucus hypersecretion in smokers with and without..., Dijkstra [/bib_ref] For example, Chand et al reported that a genetic variant of p53 plays a role in determining chronic mucus hypersecretion. [bib_ref] A genetic variant of p53 restricts the mucous secretory phenotype by regulating..., Chand [/bib_ref] Such mucus hypersecretion can affect the clinical manifestations of COPD, bronchial asthma, bronchiectasis, and other common respiratory diseases.

## Airway mucus hypersecretion and chronic airway inflammatory disease
Airway mucus hypersecretion can obstruct the respiratory tract lumen, limit airflow, and accelerate decline in lung function. [bib_ref] The presence of chronic mucus hypersecretion across adult life in relation to..., Allinson [/bib_ref] At the same time, inflammatory responses compromise mucus clearance by cilia, remove alveolar surface active substances such as surfactants, and alter biophysical properties of mucus. [bib_ref] Surfactant and lung inflammation, Reid [/bib_ref] This can lead to recurrent airway infection, causing further airway obstruction and remodeling, thereby creating a vicious cycle. Current evidence supports the notion that chronic inflammation causes mucus hypersecretion, which then plays a role in chronic airway inflammatory diseases.

## Airway mucus hypersecretion and copd
COPD is a common disease, the main clinical feature of which is persistent, progressive airflow limitation that is associated with chronic abnormal inflammatory responses to harmful particles or gases in the respiratory tract and lungs. 14 COPD seriously affects patients' ability to work and their quality of life, and it is associated with high mortality. Large epidemiological surveys in the People's Republic of China indicate a COPD prevalence of ~8.2% in adults aged .40 years. [bib_ref] Prevalence of chronic obstructive pulmonary disease in China: a large, population-based survey, Zhong [/bib_ref] Airway mucus hypersecretion manifests clinically as chronic cough and expectoration. Individuals with such symptoms are nearly 3 times more likely to suffer COPD than healthy individuals, and these symptoms may be unrelated to smoking; indeed, paroxysmal cough is an independent risk factor for COPD. [bib_ref] Incidence of chronic obstructive pulmonary disease in a cohort of young adults..., De Marco [/bib_ref] [bib_ref] Productive cough is an independent risk factor for the development of COPD..., Yamane [/bib_ref] Patients with COPD have significantly more goblet cells in airway epithelium than controls, and they secrete significantly more mucoprotein; 18 nearly 50% of COPD patients have airway mucus hypersecretion. [bib_ref] Factors associated with increased risk of exacerbation and hospital admission in a..., Miravitlles [/bib_ref] Clogged airway by mucus leads to reduced airflow and then plays a role in the pathogenesis of COPD. COPD patients are at 3.5-fold greater risk of dying if they have airway mucus hypersecretion than if they do not. [bib_ref] Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from..., Hogg [/bib_ref] In patients with airway mucus hypersecretion and COPD, accelerated decline in lung function is associated with a high rate of hospitalization and acute exacerbation of COPD. Patients with chronic cough and expectoration exhibit a significantly higher incidence of acute exacerbation, which is mostly induced by bacterial and viral infection. [bib_ref] Cough and sputum production are associated with frequent exacerbations and hospitalizations in..., Burgel [/bib_ref] [bib_ref] Acute COPD exacerbations, Wedzicha [/bib_ref] [bib_ref] Mechanisms of chronic obstructive pulmonary disease exacerbations, Wedzicha [/bib_ref] The motions involved in chronic cough and expectoration may accelerate dynamic lung hyperinflation, which may help explain why chronic cough and expectoration are independent risk factors for reduced exercise capacity in COPD patients. [bib_ref] Chronic bronchitis leads to accelerated hyperinflation in COPD patients during exercise, Zhang [/bib_ref] In addition, among subjects with COPD, those with chronic mucus hypersecretion (chronic bronchitis phenotype) present worse quality of life symptoms and mental well-being than do those without chronic mucus hypersecretion. [bib_ref] Chronic bronchitis is associated with worse symptoms and quality of life than..., Meek [/bib_ref] The important role of airway mucus hypersecretion in COPD should be fully recognized. [bib_ref] Cough and sputum production as risk factors for poor outcomes in patients..., Miravitlles [/bib_ref] 

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Airway mucus hypersecretion in chronic airway inflammatory disease hypersecretion, via chronic cough and expectoration, reduces airflow and exercise capacity and increases the risk of acute exacerbation, mortality, and poor prognosis in COPD patients.

## Airway mucus hypersecretion and bronchial asthma
Bronchial asthma, often referred to simply as "asthma," is a chronic airway inflammatory disease, the main clinical feature of which is reversible airflow limitation.Those with asthma show obviously lower mucociliary clearance from airways than patients in controls. [bib_ref] The effect of inflammation on mucociliary clearance in asthma: an overview, Donno [/bib_ref] Approximately 20%-40% of patients have increased sputum volume and symptoms of airway mucus hypersecretion, and their airway mucus is more viscous than that in patients with COPD; in addition, their airways are easily obstructed by colloidal mucus plugs. [bib_ref] Prognostic factors of asthma severity: a 9-year international prospective cohort study, De Marco [/bib_ref] Cough and expectoration are more obvious in moderate or severe asthma or uncontrollable asthma; these symptoms can serve as a phenotype and prognostic indicator. [bib_ref] Chronic cough and sputum production are associated with worse clinical outcomes in..., Thomson [/bib_ref] [bib_ref] Phenotypic determinants of uncontrolled asthma, Siroux [/bib_ref] An autopsy study of 93 patients with fatal asthma found that nearly all had mucus-obstructed airways, leading investigators to conclude that asthma-related mortality, particularly among patients with severe asthma, may be due to airway mucus hypersecretion. [bib_ref] Characterization of airway plugging in fatal asthma, Kuyper [/bib_ref] [bib_ref] Marked goblet cell hyperplasia with mucus accumulation in the airways of patients..., Aikawa [/bib_ref] The symptoms of asthma may be difficult to control because airway mucus hypersecretion facilitates bacterial colonization of airways, limits airflow, and compromises ventilation.

## Airway mucus hypersecretion and bronchiectasis
Bronchiectasis is bronchial deformation and persistent bronchial expansion caused by the destruction of smooth muscles and elastic tissues on the bronchial wall due to chronic purulent inflammation and fibrosis of the bronchus and surrounding lung tissues. 34 Cough occurs in .90% of patients with bronchiectasis, and expectoration occurs as a complication in 75%-100% of patients with cough. Patients with bronchiectasis show reduced mucociliary activities in the airway and reduced expectoration ability, and the biophysical properties of their mucus are altered, eg, it is more viscous. [bib_ref] The influence of purulence on ciliary and cough transport in bronchiectasis, Tambascio [/bib_ref] The long-term accumulation of mucus in the airway facilitates colonization by bacteria as well as recurrent cough and expectoration. [bib_ref] The influence of purulence on ciliary and cough transport in bronchiectasis, Tambascio [/bib_ref] In this way, airway mucus hypersecretion is a fundamental pathophysiological and clinical feature of bronchiectasis. Linked with airway mucus hypersecretion, airway inflammation and damage occur in bronchiectasis patients, seriously affecting patients' quality of life. [bib_ref] The Sputum Colour Chart as a predictor of lung inflammation, proteolysis and..., Goeminne [/bib_ref] 

## Airway mucus hypersecretion and pulmonary cystic fibrosis
Pulmonary cystic fibrosis is a congenital lung disease often associated with mutation in the cystic fibrosis transmembrane conductance regulator, responsible for producing sweat, digestive juices, and various mucus fluids.Patients with pulmonary cystic fibrosis show severe airway mucus hypersecretion, and many suffer recurrent pulmonary infections, which can accelerate decline in the lung function. Patient sputum is characterized by obvious neutrophil infiltration, cellular DNA released from injured cells, and abundant Pseudomonas aeruginosa.Patients also show substantial epithelial goblet cell metaplasia in the airway in contrast to healthy individuals, as well as significantly higher MUC5AC expression.Airway mucus hypersecretion in patients with pulmonary cystic fibrosis is associated with persistent cough, expectoration, and dyspnea.
The preceding sections summarize the close relationship of airway mucus hypersecretion with incidence, progression, and prognosis of common chronic airway inflammatory diseases. Full recognition of the role of airway mucus hypersecretion in these diseases is important for guiding clinical treatment.

## Evaluation of airway mucus hypersecretion
Airway mucus hypersecretion manifests mainly as chronic cough and expectoration, which are particularly obvious during stimulation, weather changes, and exacerbation of infection. The severity of cough and the volume and properties of sputum serve as an index of airway mucus hypersecretion, which can fluctuate during periods of stability or acute exacerbation of airway diseases. The cough and sputum assessment questionnaire (CASA-Q) designed by Crawford et al is one of the few tools available for assessing airway mucus hypersecretion. [bib_ref] Development and validation of a cough and sputum assessment questionnaire, Crawford [/bib_ref] The questionnaire contains 4 sections covering coughing, sputum, and their effects. Lower overall score indicates more severe airway mucus hypersecretion. CASA-Q score is closely related to the quality of life and clinical symptoms of COPD patients, and it is useful for monitoring recovery from acute COPD exacerbations. [bib_ref] Development and validation of a cough and sputum assessment questionnaire, Crawford [/bib_ref] [bib_ref] Responsiveness of the cough and sputum assessment questionnaire in exacerbations of COPD..., Monz [/bib_ref] In addition, St George's Respiratory Questionnaire and American Thoracic Society Questionnaire, important questionnaires that are used for many cohorts around the world and also contain questions for evaluation of cough and sputum, can also be used to evaluate airway mucus hypersecretion. [bib_ref] Validation of a respiratory symptom questionnaire in adolescent smokers, Cassidy [/bib_ref] All these questionnaires may be used to evaluate airway mucus hypersecretion and to define the questionnaire with best efficacy. No standardized methods exist for quantitating airway mucus hypersecretion in COPD patients, which requires invasive procedures and so is rarely performed in the clinic. Since cough and expectoration

## Treatment of airway mucus hypersecretion
At present, chronic airway inflammatory diseases such as COPD and asthma are treated mainly using bronchodilators to open occluded airways or by using corticosteroid inhalation to control inflammation. [bib_ref] Advances in mucous cell metaplasia: a plug for mucus as a therapeutic..., Curran [/bib_ref] [bib_ref] Revisited role for mucus hypersecretion in the pathogenesis of COPD, Cerveri [/bib_ref] Given the important clinical significance of airway mucus hypersecretion in chronic airway inflammatory diseases, expectorant therapy is widely used to help relieve airway stenosis, avoid recurrent infection and exacerbation, and delay decline in lung function.

## Drug therapies (expectorants)
Expectorants are drugs that promote mucus activity, alter mucus viscosity, and/or promote mucus clearance. [bib_ref] Mucoactive drugs, Balsamo [/bib_ref] Drugs promoting mucus activity can be classified into the following categories [fig_ref] Table 1: Mucoactive drugs and their potential mechanism of action [/fig_ref] : 1) expectorants that remove mucus from the respiratory tract (hypertonic normal saline and woundhealing glycerol ether); 2) mucoregulators that alter mucus secretion (carbocysteine and macrolides); 3) mucolytics that reduce mucus viscosity (N-acetylcysteine, erdosteine, and fudosteine); and 4) mucokinetic agents (bronchodilators, myrtle oil, and ambroxol). Each category is discussed in more detail below.

## Expectorants
Hypertonic saline helps clear sputum, and administering 7% hypertonic saline to patients with pulmonary cystic fibrosis accelerates mucus discharge and improves airflow and lung function. [bib_ref] Mucus clearance and lung function in cystic fibrosis with hypertonic saline, Donaldson [/bib_ref] [bib_ref] A controlled trial of long-term inhaled hypertonic saline in patients with cystic..., Elkins [/bib_ref] Aerosol inhalation of 7% hypertonic saline as an auxiliary therapy can promote mucus discharge and improve lung function and quality of life in patients with bronchiectasis. [bib_ref] Nebulised 7% hypertonic saline improves lung function and quality of life in..., Kellett [/bib_ref] Studies in mouse models of COPD suggest that hypertonic saline can help prevent and treat airway mucus hypersecretion, but its value in patients remains to be demonstrated. [bib_ref] Hypertonic saline is effective in the prevention and treatment of mucus obstruction,..., Graeber [/bib_ref] Further study has shown that some COPD patients suffer further airway stenosis while receiving 3% hypertonic saline. [bib_ref] Airway response to inhaled hypertonic saline in patients with moderate to severe..., Taube [/bib_ref] In fact, patients with different types of chronic airway inflammatory diseases respond differently to hypertonic saline, and especially some COPD patients develop dyspnea when receiving atomizing hypertonic saline. [bib_ref] Airway response to inhaled hypertonic saline in patients with moderate to severe..., Taube [/bib_ref] Therefore, hypertonic saline treatment should be used in accordance with its clinical indications.

## Mucoregulators
A multicenter study involving a 1-year follow-up published in 2008 reported that carbocysteine (500 mg, 3 times daily) significantly reduced the frequency of acute COPD exacerbations and that health-related quality of life was significantly higher in COPD patients than in controls. [bib_ref] Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE..., Zheng [/bib_ref] Another study supported the idea that carbocysteine can significantly reduce the frequency of acute exacerbations, reduce the frequency of catching colds, and improve the quality of life in COPD patients. [bib_ref] Carbocisteine reduces frequency of common colds and exacerbations in patients with chronic..., Yasuda [/bib_ref] As a result, carbocysteine is the drug recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) for treating COPD. Carbocysteine (500 mg, 3 times daily) can also improve the cough threshold and relieve cough symptoms in asthma patients, and it is the recommended treatment for cough-variant asthma. [bib_ref] Effect of carbocysteine on cough reflex to capsaicin in asthmatic patients, Ishiura [/bib_ref] Macrolides, in addition to their antibacterial activity, show good immunomodulatory activity and can inhibit inflammation and airway mucus hypersecretion.Long-term

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Airway mucus hypersecretion in chronic airway inflammatory disease administration of erythromycin (250 mg, twice daily), azithromycin (250 mg, once daily), and other macrolides helps reduce the frequency of acute exacerbations in COPD patients and improves their quality of life, and evidencebased medicine has also confirmed the clinical value of macrolides for reducing the occurrence of acute COPD exacerbations. [bib_ref] Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations, Seemungal [/bib_ref] [bib_ref] Azithromycin for prevention of exacerbations of COPD, Albert [/bib_ref] [bib_ref] Macrolide therapy decreases chronic obstructive pulmonary disease exacerbation: a meta-analysis, Yao [/bib_ref] Although no official guidelines include macrolides among classical expectorants, the available evidence suggests that macrolides can be recommended for achieving antibiotic effects and sputum clearance in COPD patients who require antibiotics. [bib_ref] Long-term macrolide treatment for chronic respiratory disease, Spagnolo [/bib_ref] Evidence also suggests that macrolides have limited ability to improve lung function, but they can improve airway hyperresponsiveness in asthma patients. [bib_ref] Macrolides for the long-term management of asthma -a meta-analysis of randomized clinical..., Reiter [/bib_ref] In bronchiectasis patients, the macrolides erythromycin (250 mg, twice daily after conversion) and azithromycin (250 mg, once daily) can help alleviate acute exacerbations in patients with infective COPD. [bib_ref] Effect of long-term, lowdose erythromycin on pulmonary exacerbations among patients with non-cystic..., Serisier [/bib_ref] [bib_ref] Effect of azithromycin maintenance treatment on infectious exacerbations among patients with non-cystic..., Altenburg [/bib_ref] The combination of roxithromycin (150 mg, once daily) and ambroxol can improve bronchiectasis and dyspnea scores in the stable phase of the disease.The available evidence suggests that macrolides help reverse the exacerbation of pulmonary symptoms in bronchiectasis patients. [bib_ref] Effectiveness and safety of macrolides in bronchiectasis patients: a meta-analysis and systematic..., Shi [/bib_ref] Macrolides can be recommended for long-term use in some bronchiectasis patients with severe symptoms of airway mucus hypersecretion; these patients benefit from the compounds' dual effects as antibiotics and immunomodulators.

## Mucolytics
N-acetylcysteine is a classic antioxidant that can reduce mucus viscosity and promote mucus discharge.In COPD patients, high-dose N-acetylcysteine (600 mg, twice daily) can significantly improve lung function, reduce the frequency of acute COPD exacerbations, delay readmission, and enhance small airway function. [bib_ref] High-dose N-acetylcysteine in stable COPD: the 1-year, double-blind, randomized, placebo-controlled HIACE study, Tse [/bib_ref] A randomized controlled trial of 1,006 patients aged 40-80 years and treated at 34 Chinese hospitals for moderate or severe COPD confirmed that long-term, high-dose N-acetylcysteine (600 mg, twice daily) can effectively prevent acute COPD exacerbations. [bib_ref] Twice daily N-acetylcysteine 600 mg for exacerbations of chronic obstructive pulmonary disease..., Zheng [/bib_ref] Even patients with moderate COPD benefited significantly. GOLD indicates that N-acetylcysteine can be used to prevent acute COPD exacerbations. Little evidence exists for or against the use of N-acetylcysteine in patients with asthma, pulmonary cystic fibrosis, or bronchiectasis; large, rigorous trials are needed to examine safety and efficacy in these populations. Erdosteine, another mucolytic, can promote mucus discharge and improve lung function in elderly patients with bronchiectasis and chronic airway mucus hypersecretion.Fudosteine is used to treat chronic respiratory diseases, such as bronchial asthma, chronic bronchitis, pulmonary emphysema, COPD, and bronchiectasis. It works as a mucoactive agent by inhibiting MUC5AC gene expression and related signaling pathways. [bib_ref] Effect of fudosteine on mucin production, Rhee [/bib_ref] [bib_ref] Effect of fudosteine, a cysteine derivative, on airway hyperresponsiveness, inflammation, and remodeling..., Ueno-Iio [/bib_ref] Fudosteine has been shown to inhibit peroxynitrite-induced airway nitrosative stress in lung epithelial cells by direct scavenging of peroxynitrite and plays a protective role in COPD. [bib_ref] Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by..., Osoata [/bib_ref] These findings suggest that fudosteine may be useful for controlling oxidative/carbonyl stress-related mucus secretion in patients with asthma, bronchiectasis, or COPD. [bib_ref] Antioxidant pharmacological therapies for COPD, Rahman [/bib_ref] 

## Mucokinetic agents
The prokinetic agent most widely used in the clinic is ambroxol, which can stimulate surfactant production in the respiratory tract, regulate secretion of serous and mucus fluids, improve mucus clearance in the ciliated and nonciliated areas of the respiratory tract, reduce phlegm and ciliary adhesion, and facilitate expectoration. [bib_ref] Ambroxol in the 21st century: pharmacological and clinical update, Malerba [/bib_ref] Long-term ambroxol (75 mg, twice daily) can reduce the frequency of acute exacerbations in patients with severe COPD. [bib_ref] Effect of twelve-months therapy with oral ambroxol in preventing exacerbations in patients..., Malerba [/bib_ref] It can also benefit patients who experience acute exacerbations by alleviating oxidative stress reactions.Recent work suggests that ambroxol can work synergistically with antibiotics in a rat model of catheter-associated P. aeruginosa infection. [bib_ref] Effects of combined treatment with ambroxol and ciprofloxacin on catheter-associated Pseudomonas aeruginosa..., Lu [/bib_ref] Oral and injected ambroxol can be used in COPD outpatients and inpatients receiving expectorant therapy, particularly those with viscous sputum and expectoration difficulties. The usual dose is 30 mg, 3 times daily; this can be adjusted based on clinical conditions. Ambroxol can improve lung function and shorten hospitalization for bronchiectasis patients with infections.The main components of myrtle oil expectorants are eucalyptol and limonene; they also contain pinene and standard myrtle oil. Standard myrtle oil can restore mucociliary clearance in the upper and lower respiratory tracts, thereby thinning and alkalifying mucus, enhancing mucociliary movement, significantly accelerating mucus motility, and promoting sputum discharge in a rat model of COPD. [bib_ref] Effect of Myrtol standardized on mucus hypersecretion and clearance of Pseudomonas aeruginosa..., Cao [/bib_ref] The combination of standard myrtle oil and routine treatment has been shown to accelerate mucus motility in COPD patients more than routine treatment on its own, as well as improve blood gas composition.Myrtle oil is often used as an expectorant for COPD patients with expectoration difficulties (eucalyptol-limonene-pinene at 300 mg, 2-3 times daily; standard myrtle oil at 300 mg, 3 times daily).
Bronchodilators dilate the bronchus and reduce mucus secretion. The bronchodilator tiotropium bromide, which is

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Shen et al an anticholinergic agent, can effectively suppress goblet cell metaplasia induced by neutrophil elastase and mucin secretion; this implies that its therapeutic effects may involve suppressing airway mucus hypersecretion in mice; thus, tiotropium bromide can also be classified as a mucus regulator. [bib_ref] Inhibition of neutrophil elastase-induced goblet cell metaplasia by tiotropium in mice, Arai [/bib_ref] Consistent with this idea, formoterol, one of the long-acting  2 -receptor agonists, may inhibit airway goblet cell hyperplasia and MUC5AC expression and reduce airway mucus hypersecretion in asthmatic mice. [bib_ref] The effect of formoterol on airway goblet cell hyperplasia and protein Muc5ac..., Tan [/bib_ref] The combination of  2 agonist formoterol and tiotropium bromide can accelerate airway mucus clearance, dilate the bronchus, alleviate airway stenosis, suppress mucin synthesis, and promote ciliary motions and mucus discharge in COPD patients. [bib_ref] Effects of formoterol and tiotropium bromide on mucus clearance in patients with..., Meyer [/bib_ref] Respiratory wards in hospitals have begun routinely combining bronchodilators and expectorants to treat COPD. In the People's Republic of China, acute COPD exacerbations are routinely treated using the combination of aerosol inhalation of isopropyl bromide and intravenous injection of ambroxol. This treatment promotes sputum discharge, alleviates symptoms of airway obstruction such as hypoxia and dyspnea, and increases clinical efficacy in patients with acute COPD exacerbation.A systematic review of 30 clinical studies involving 7,436 subjects concluded that expectorants can reduce the frequency of acute COPD exacerbations, benefiting COPD patients with a phenotype of frequent exacerbations and patients who are repeatedly admitted to hospital. [bib_ref] Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease, Poole [/bib_ref] In contrast, a large evidence base is lacking about the efficacy of expectorants in treating asthma, pulmonary cystic fibrosis, and bronchiectasis. Future studies should assess efficacy of expectorants.

## Nondrug therapies
Several nondrug therapies have been described for managing patients with chronic airway inflammatory disease and associated airway mucus hypersecretion. One therapy is smoking cessation, since tobacco smoke is one of the strongest risk factors for various respiratory diseases, including COPD and asthma. Toxic ingredients in tobacco smoke may stimulate epithelial goblet cell metaplasia in the airway as well as mucin secretion, leading to airway mucus hypersecretion. Smoking cessation may therefore cut off airway mucus hypersecretion "at the source." In the People's Republic of China, national guidelines have been published to guide efforts by health care workers to help patients stop smoking.Another nondrug therapy is physiotherapy, in which patients are taught about deep breathing and effective coughing, or they receive chest percussion, postural expectoration, and inhalation therapies. Inhalation therapies, which can be administered via humidified inhalation or aerosol inhalation, can moisturize the airway, dilute sputum, facilitate expectoration, and prevent sputum scab formation. Such therapies are widely used to treat common respiratory tract diseases because they provide obvious benefits with few, if any, adverse reactions.Effective mucus discharge requires different body positions depending on the site of a patient's lesion, [bib_ref] Positioning versus postural drainage, Fink [/bib_ref] and this postural drainage must be taught to patients. Appropriate body positions help the mucus flow from focus to large airway then to bronchus and help to get mucus out of the airway, and then, they play a role in mucus discharge. Patients with lesions in the right upper apical segment should expectorate while sitting in a vertical or inclined position and leaning slightly to the left. Patients with lesions in the right upper anterior segment should expectorate while supine with the right back slightly elevated. Patients with lesions in the right upper posterior segment should expectorate while in a left supine position and turning left by 45, with a cushion placed in front to support the posture. Patients with lesions in the right middle segment should expectorate while supine with the chest and abdomen turned to the left by 45, with a cushion placed behind to support the posture and with the right end of the bed elevated. Patients with lesions in the left upper posterior apical segment should expectorate while in the vertical sitting position or semi-supine position, with the body leaning to the right by 45 and with a cushion placed behind to support the posture. Patients with lesions in the left upper anterior segment and lingular segment should be supine, with the chest and abdomen turned to the right by 45, with a cushion placed behind to support the posture and the left end of the bed elevated. Patients with lesions in the left lower dorsal segment should be prone, leaning slightly with the affected side upward and the head lowered. Patients with lesions in the left lower basal segment should be prone, leaning by 45 with the affected side upward, the head downward, and the chest upward; alternatively, they can adopt a contralateral supine position with the chest and abdomen turned to the right by 45, the head lowered and facing downward and the feet pointing upward .
A third nondrug therapy is high-frequency chest wall oscillation. This is often used to enhance airway mucus clearance in patients with pulmonary cystic fibrosis and bronchiectasis, and it can significantly improve the quality of life in COPD patients and reduce sputum volume. [bib_ref] A pilot study of the impact of high-frequency chest wall oscillation in..., Chakravorty [/bib_ref] Intermittent positive end-expiratory pressure (PEEP) can dilate the small airway, reduce small airway obstruction, promote the sputum drainage and discharge, and accelerate mucus clearance in COPD patients. Performing PEEP twice daily for 15 minutes each time during 10 days can promote expectoration and

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Airway mucus hypersecretion in chronic airway inflammatory disease reduce mucus density and production of purulent sputum; therefore, it may be useful for COPD patients with symptoms of airway mucus hypersecretion. 86

## Future studies and expectations
Airway mucus hypersecretion is an important driver of airway obstruction, rapid decline in lung function, and increased frequency of acute exacerbation in patients with chronic airway inflammatory diseases; it is closely related to patient prognosis. Detailed investigation into the signaling pathways and downstream effector molecules involved in airway mucus hypersecretion will improve our understanding and the treatment of these chronic diseases. One challenge is to systematically explore how to combine traditional drugs with classic expectorants and how to combine expectorants to achieve optimal therapeutic effects. Clinicians should recognize the benefits of expectorant therapies for patients with chronic airway inflammatory diseases and should continuously seek to improve and innovate treatments for such patients.
[table] Airway mucus: International Journal of COPD 2018:13 submit your manuscript | www.dovepress.com [/table]
[table] Table 1: Mucoactive drugs and their potential mechanism of action [/table]