Role of mucoactive agents and secretion clearance techniques in COPD

INTRODUCTION — Tracheobronchial mucus contributes significantly to the symptoms of chronic obstructive pulmonary disease (COPD) and is a defining feature of the condition [1]. Chronic mucus hypersecretion is a major cause of airflow obstruction in COPD and is associated with increased mortality, an accelerated decline of forced expiratory volume in one second (FEV₁), reduced quality of life, and increased risk of exacerbations and hospitalizations [2].

The role of mucoactive therapy in the management of COPD will be reviewed here. The role of mucoactive agents in the treatment of cystic fibrosis (CF) lung disease and non-CF bronchiectasis is discussed separately.

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Bronchiectasis in adults: Maintaining lung health".)

●(See "Bronchiectasis in adults: Treatment of acute and recurrent exacerbations".)

DEFINITION — A mucoactive drug is defined as an agent with the capability of modifying mucus production, secretion, its nature and composition, or its interactions with the mucociliary epithelium [3]. Examples of mucoactive drugs include expectorants (induce cough or increase the volume of secretions), mucolytics (reduce the viscosity of mucus), mucokinetic drugs (increase the mobility and transportability of mucus), and mucoregulators (control the process of hypersecretion) [4].

PROPERTIES OF MUCUS — The surface liquid covering the epithelial lining of the airways comprises at least two layers: the mucus layer (gel) and the periciliary layer surrounding the cilia [5,6]. In contrast to traditional models where the periciliary layer is assumed to be liquid (sol), a more recent model considers it as consisting of a gel mesh of cell-tethered mucins and polysaccharides [7]. Mucus consists of a mixture of transudative fluid and secretions from surface epithelium and submucosal glands. It is predominantly composed of water (95 percent) and glycoproteins (2 to 3 percent), with smaller components of proteoglycans (0.1 to 0.5 percent), lipids (0.3 to 0.5 percent), proteins, and DNA [8]. The glycoprotein component consists of secreted mucins, particularly the large polymeric structures MUC5AC and MUC5B, which account for the rheologic properties (ie, properties governing flow) of mucus [9].

Mucus is a movable barrier that maintains hydration and contains defense factors against various pathogens [9]. The normal volume of mucus secretion is approximately 15 mL/day [10], with a mucociliary clearance of 50 micrometers/second [11].

Tracheobronchial mucus behaves as a non-Newtonian fluid with viscoelastic properties [10]. The liquid-like, viscous properties allow the mucus to be extruded by glands, whereas the solid-like, elastic properties permit the transfer, storage, and conversion into motion of the energy imparted by the moving cilia. Glycoproteins are essential for this elasticity of mucus. A surfactant layer between the mucus gel and periciliary sol acts as a lubricant that also facilitates the transfer of energy from beating cilia to mucus [12].

Mucus secretion can increase three-fold in COPD and 10-fold in cystic fibrosis [5]. Mucus composition can also change in disease states. For instance, concentrations of MUC5B and MUC5AC increase 3-fold and 10-fold respectively in ever smokers with severe COPD relative to controls [11]. Further, DNA can contribute up to 10 percent of the dry weight of mucus secretions in cystic fibrosis [13]. The hydration of mucus also declines with disease states, from a 95 percent normal water composition, to 90 percent in smokers, and <83 percent in cystic fibrosis [14]. A contributing factor to the dehydration of airway mucous may be internalization of the cystic fibrosis transmembrane conductance regulator (CFTR) with cigarette smoking [14]. As the mucin concentration increases in disease states, mucociliary clearance declines, until a threshold following which adherent secretions may only be managed by cough clearance [11]. Uncleared mucus otherwise contributes to airway obstruction and to the risk for infection [11]. The importance of mucus secretion in the pathophysiology of disease is highlighted by the finding that total mucin concentration predicts traditionally defined chronic bronchitis, and may serve a biologic marker for this otherwise clinically defined disease [11]. Further, mucus hypersecretion, upregulation of MUC5AC and MUC5B, cross-linking and entanglement of mucin polymers, reduced mesh network pore size, and decreased mucus clearance all contribute to airway obstruction, infection risk, and lung function decline [15].

In determining the ability of an agent to promote clearance of secretions, both mucociliary clearance and cough clearance need to be addressed. Different rheologic properties have been reported to have different and potentially antagonistic effects on these two mechanisms of mucus transport. As an example, mucus clearance requires effective transfer of the kinetic energy from beating cilia to the mucus. In that regard, factors that improve mucociliary transport include: a higher mucus elasticity (to store the transmitted energy), lower mucus viscosity (to reduce loss of energy), higher adhesivity (that hinders wave formation in the gel layer), increased spinnability (a measure of the thread forming ability of mucus), increased ciliary beat frequency, a thinner mucus layer, and a periciliary (sol) layer that is just less than the height of the cilia (to improve coupling with ciliary tips) [4,16,17].

In contrast, factors that improve cough clearance include: a higher mucus viscosity, lower mucus elasticity (to reduce recoil of cough-sheared mucus), lower adhesivity (to promote wave formation in the gel), lower spinnability (ability to be spun into a thread), a thicker mucus layer, and a periciliary layer that is higher than the height of the cilia [4,18]. However, these general concepts may not always apply across disease states. For instance, in one study of mucus transport in patients with cystic fibrosis, the elastic modulus (capacity to be deformed elastically) was found to be negatively correlated with mucociliary transport, whereas contact angle (a reflection of surface tension associated with the adhesive properties of mucus: a higher contact angle reflects poor wettability and poor adhesiveness) was negatively correlated with cough clearance [19].

Disease states may affect the rheological properties of mucus [20]. For instance, the levels of the gel-forming mucins, MUC5AC and MUC5B, are elevated in the airways and sputum of individuals with chronic respiratory diseases [11], and may contribute to the viscoelastic properties of mucus [8]. Increased purulence of sputum results in increased viscosity, surface tension, elastic modulus, contact angle, and in decreased cough transport, but these effects may be secondary to decreased water content [19]. Patients with asthma appear to have the highest sputum viscosity, while patients with cystic fibrosis have lower viscosity [4]. Patients with chronic bronchitis and bronchiectasis have sputum with intermediate viscosities [4].

Subsequent attention has focused upon the role of the periciliary layer. Studies have shown that transport of the periciliary layer is mucus dependent. This suggests that new therapies for the treatment of excess respiratory mucus should focus on the restoration of airway surface liquid volume rather than alteration of its tonicity [5,21].

MUCOACTIVE EFFECTS OF ROUTINE TREATMENTS FOR COPD — In chronic obstructive pulmonary disease (COPD), the most important intervention to reduce sputum production is cigarette smoking cessation [22]. Some routine therapies for COPD, in addition to their bronchodilator or anti-inflammatory effects, also have mucoactive effects.

Bronchodilators act as mucokinetic agents by improving airflow and facilitating mucus clearance. The different types of bronchodilators have additional, more specific effects that may be either beneficial or detrimental.

Beta agonists — Beta agonists improve clearance of airway mucus largely via an effect on ciliary beat frequency. As an example, aerosolized isoproterenol (a potent sympathomimetic amine with almost exclusive beta-adrenergic activity) increases mucus clearance, presumably from increased ciliary beat rate [23]. This effect is not due to bronchial vasodilation, the presence of aqueous aerosol droplets, reflex parasympathetic activation, or bronchodilation [23,24].

Anticholinergics — The anticholinergic agent atropine is an effective antisialagogue (reduces saliva secretion) that results in significant reductions in tracheal mucus velocity and mucociliary transport [25,26]. However, it has no effect on mucus secretory rate [25].

Ipratropium bromide does not appear to have the same effects as atropine. As an example, studies in humans have not detected changes in the clearance of secretions or in sputum volume or viscosity [27], while animal studies have shown only minimal depression of ciliary beat frequency and tracheal mucus velocity, with no effect on volume or viscoelastic properties [25]. Thus, ipratropium bromide can improve airway obstruction without negatively affecting mucociliary clearance [24].

In small studies, the effect of tiotropium on mucociliary clearance (as measured by radioaerosol clearance) was not different from placebo, but tiotropium was inferior to formoterol [28,29]. It is not known whether this is a clinically important effect.

Methylxanthines — Methylxanthines (eg, theophylline) stimulate ciliary beat frequency and increase water flux toward the lumen, which should improve mucus clearance, but they also increase mucus secretion in the lower airways [30]. However, some of these effects depend on a relatively high dose that causes gastric irritation (and thus a vagally-mediated increase in airway secretions), rather than on the bronchodilator effect. Overall, oral aminophylline increases tracheobronchial mucociliary clearance in patients with COPD, but this effect is not associated with identifiable improvement in pulmonary function or cough [31]. The role of methylxanthines in COPD is more related to improvement in exercise tolerance than to improved secretion clearance or reduction in the frequency of exacerbations.

Phosphodiesterase inhibitors — The phosphodiesterase (PDE)4 inhibitor roflumilast, although not a mucoactive agent, was found to be most effective in patients with repeated exacerbations of COPD and with a chronic bronchitis phenotype, consisting of high cough or sputum scores [32]. Randomized trials have confirmed that the use of roflumilast in such patients reduced the exacerbation frequency, improved the FEV₁, and improved the dyspnea scores [33].

Inhaled glucocorticoids — Glucocorticoids can act as a mucoregulator by affecting the underlying cause of mucus hypersecretion. Aerosolized beclomethasone at doses >800 mcg/day has been shown to produce a significant improvement in spirometry in patients with chronic bronchitis [34]. The benefit appears to result from control of airway inflammation since beclomethasone does not affect mucociliary clearance [35]. (See "Role of inhaled glucocorticoid therapy in stable COPD".)

MUCOACTIVE STRATEGIES FOR SELECTED PATIENTS — Types of mucoactive agents that may be helpful in selected patients with refractory symptoms include systemic antibiotics and thiol preparations (eg, N-acetylcysteine, erdosteine, carbocysteine).

Antibiotics — Certain antibiotics are thought to have mucoactive effects beyond their antimicrobial effects. Potential mechanisms of action may include inhibition of proinflammatory cytokines or immunomodulation of antiinflammatory effects [36-38].

An indirectly mucoactive effect is seen in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) associated with changes in sputum volume or color, when antibiotics are used to reduce the bacterial load that contributes to inflammation and increased sputum production. (See "COPD exacerbations: Management", section on 'Antiviral and antimicrobial agents'.)

In addition, macrolide antibiotics may have an anti-inflammatory effect that reduces mucus secretion independent of antimicrobial activity [36]. A possible example of this anti-inflammatory effect is the beneficial effect of erythromycin in diffuse panbronchiolitis, a disease with copious sputum production, at doses below those usually considered antimicrobial. (See "Diffuse panbronchiolitis", section on 'Erythromycin'.)

Macrolide and fluoroquinolone antibiotics have been found to reduce the frequency of exacerbations in certain patients with COPD, although careful patient selection and monitoring are needed to reduce adverse effects. (See "Management of infection in exacerbations of chronic obstructive pulmonary disease", section on 'Prophylactic macrolides' and "Management of refractory chronic obstructive pulmonary disease", section on 'Macrolides and other chronic antibiotic therapy'.)

Thiols and thiol derivatives — Agents that sever disulfide bridges (eg, N-acetyl-L-cysteine (aka acetylcysteine or NAC), S-carboxymethyl cysteine (carbocysteine), 2-mercaptoethane sulfonate, and erdosteine) act directly on mucoproteins, liquefying mucus and lowering its viscosity. In addition, they may have other potentially relevant antioxidant, anti-inflammatory, and antibacterial properties [10,39,40]. Recommendations from systematic reviews and clinical guidelines regarding mucolytics are predominantly based on this class of agents [1,41,42].

Side effects of thiol preparations include nausea, vomiting, and allergic reactions.

N-acetylcysteine (NAC) — N-acetylcysteine liquefies mucus and DNA (via disruption of disulfide bonds) and has antioxidant effects when used at an adequate dose. However, given the small and inconsistently demonstrated clinical benefits and the potential for adverse effects, we do not routinely use oral NAC in patients with COPD.

In a systematic review, mucolytics (strongly represented by NAC in the trials analyzed) resulted in one fewer exacerbation every three years, reduced disability by 0.43 days per participant per month, and had a small favorable effect on quality of life that did not reach the minimally clinically important difference [41]. Trials specifically examining the effects of oral NAC in patients with COPD have yielded conflicting results [43-52] and do not show benefit in a meta-analysis [53]; however, there is more consistent evidence of benefit in trials using high doses of oral NAC:

●The Placebo-controlled study on efficacy and safety of N-acetylcysTeine High-dose in Exacerbations of chronic Obstructive pulmoNary disease (PANTHEON) trial randomly assigned 1006 Chinese patients with moderate to severe COPD (forced expiratory volume in one second [FEV₁] of 30 to 70 percent of predicted) to NAC (600 mg) or placebo, twice daily for one year [54]. A reduction in exacerbations was noted in the NAC group (risk ratio 0.78, 95% CI 0.67-0.90), but pulmonary function and quality of life were not significantly different between the groups. However, certain features of the trial limit the conclusions that can be drawn: Exacerbations were assessed by diary cards and may have been underreported; patients requiring supplemental oxygen or pulmonary rehabilitation were excluded from the trial; approximately 40 percent of the study population were nonsmokers; and 25 percent of participants did not complete the study.

●In a one-year trial that randomly assigned 120 patients with moderately severe COPD to high-dose NAC (1200 mg per day) or placebo, no significant improvement occurred in exercise capacity or quality of life, but the frequency of exacerbations was decreased with NAC compared with placebo (0.96 times/y versus 1.71 times/y, p = 0.019) [55]. Modest improvements were noted in the mid-expiratory flow rate (forced expiratory flow [FEF] 25 to 75 percent), but not FEV₁. The majority of those patients (>70 percent) were on inhaled glucocorticoids, raising the possibility that concurrent glucocorticoids blunted the effect of NAC.

●In a network meta-analysis of randomized trials assessing mucolytics in COPD, high-dose NAC (1200 mg per day) protected against exacerbations when compared with placebo (odds ratio 0.56, 95% CI 0.35–0.92), whereas lower dose NAC (600 mg per day) did not [56].

Reasons for the discrepancy between the various studies may include a dose dependent effect of NAC (eg, lack of antioxidant properties at doses under 1200 mg daily), poor penetration into bronchoalveolar fluid when administered orally, and reduced effect in patients on inhaled glucocorticoids [55,57]. Doses of NAC up to 3000 mg per day were considered to be safe and well tolerated, with a similar safety profile regardless of dose [58].

In early studies, NAC was administered via inhalation or direct instillation during bronchoscopy, as NAC causes liquefaction of mucus within one minute of direct application with a maximal effect at five to ten minutes [59]. However, nebulized NAC can cause cough or acute bronchospasm, so it is often coadministered with a beta-adrenergic agonist [58,60]. Due to the combined use of NAC and the beta agonist, it is difficult to know whether any beneficial effects on mucociliary clearance are attributable to the nebulized NAC independent from the beta-agonist [61]. NAC can also be nebulized together with bromelain (a protease enzyme found in the stem of pineapples) with reduction in viscosity and improved flow of experimental sputum compared to either agent alone [62]. (See "Management of refractory chronic obstructive pulmonary disease", section on 'Mucoactive agents'.)

Erdosteine — Erdosteine is another thiol agent with an established safety profile and generally fewer gastrointestinal side effects than other thiol derivatives. Where available, erdosteine may be an option for the management of frequent COPD exacerbations in patients who are unable to use inhaled glucocorticoids with long-acting beta agonists or long-acting muscarinic agents. However, evidence is mixed regarding reduction in exacerbations and degree of effect when used as add-on therapy to more established inhaled regimens [41].

●The EQUALIFE study, a randomized trial of 155 patients with COPD, demonstrated that compared with placebo, treated patients had a 30 percent reduction in exacerbations, a 58 percent reduction in hospital days, improved health status, and lower COPD-related diseases costs [63].

●In a separate placebo-controlled trial in 445 patients with moderate and severe COPD (the RESTORE trial), addition of erdosteine to usual care decreased the rate of mild exacerbations but not moderate or severe exacerbations [64]. Erdosteine also reduced the exacerbation duration regardless of exacerbation severity but did not improve quality of life as measured by the St. George's Respiratory Questionnaire. A post hoc analysis showed similar findings in the subset of patients with moderate (not severe) COPD [65].

●In a meta-analysis indirectly comparing mucolytic treatments in 2753 patients with COPD from seven trials, erdosteine was more effective than carbocysteine and NAC in reducing acute exacerbation number, duration, and associated hospitalizations [66]. According to this analysis, one exacerbation could be prevented for every ten patients treated for one year with erdosteine.

In addition to its mucolytic properties, erdosteine may have anti-inflammatory properties with reduced levels of leukotriene (LT) B4 and markers of oxidative stress demonstrated in one study of active smokers with COPD [67].

Carbocysteine — In the Chinese PEACE study, 709 patients with moderate-to-severe COPD were randomized in a double-blind trial to receive 500 mg carbocysteine (S-carboxymethyl cysteine) or placebo, three times a day for 12 months [68]. Compared to placebo, patients on carbocysteine had a 0.34 mean reduction in exacerbations per patient per year (1.35 versus 1.01 respectively). Quality of life as measured by the St. George's Respiratory Questionnaire was also significantly improved at 12 months.

Where available, carbocysteine may be an option for the management of frequent COPD exacerbations in patients who are unable to use inhaled glucocorticoids with long-acting beta agonists or long-acting muscarinic agents. However, there is no clear evidence that these agents effectively reduce exacerbations when used as add-on therapy to more established inhaled regimens [41].

Role of concomitant inhaled glucocorticoids — Data are conflicting regarding whether mucolytic thiol derivatives confer additional benefits in patients already on inhaled glucocorticoids (ICS) in addition to those who are ICS-naive [48,54,55]. The following are the major trials that have examined this issue:

●The PANTHEON trial, which randomly assigned 1006 patients with COPD to oral N-acetylcysteine (1200 mg/day) or placebo, stratified the randomization based on use of ICS such that approximately half the subjects were using ICS [54,69]. As noted above, a reduction in the frequency of exacerbations was noted in the NAC group, but no benefits were noted in pulmonary function or quality of life. No interaction was noted between the effect on exacerbations and the use of ICS, suggesting that patients on ICS also experienced a reduction in exacerbations. The trial did not provide the dose of ICS used by the study subjects.

●The Chinese PEACE trial (709 subjects), which found an overall reduction in exacerbations with carbocysteine compared with placebo, did not find a significant interaction on reduction of exacerbations between concomitant use of ICS and carbocysteine [68]. However, only 17 percent of PEACE study participants received ICS.

●In the BRONCUS trial (523 subjects), a reduction in exacerbations with N-acetylcysteine was only noted in the subgroup of patients who were not using ICS, which comprised 40 percent of the subjects [48]. However, this trial used half the dose of NAC compared with the other two trials.

●In the RESTORE trial of erdosteine (445 subjects) the randomization was stratified by used of ICS, but there was no significant difference in the exacerbation rate or duration in those taking ICS relative to those who did not [64]. (See 'Erdosteine' above.)

MUCOACTIVE AGENTS OF LIMITED OR NO BENEFIT — A number of modalities, including hydration, hypertonic saline inhalation, oral expectorants, oral iodide preparations, cromoglycate, and inhalation of DNase, have been utilized to alter the characteristics of mucus, but without evidence of substantial clinical efficacy.

Hydration — While maintaining normal hydration is appropriate, there is no evidence that overhydration in order to facilitate sputum production is of any benefit. One study, for example, evaluated the effect of hydration on mucus volume, viscoelastic properties of sputum, respiratory symptoms, and forced expiratory volume in one second (FEV₁): there were no differences when patients were dehydrated, were treated with hydration (1800 to 2400 mL/day), or had ad lib fluid intake [70].

Hypertonic saline — Hypertonic saline aerosols have traditionally been used to induce expectoration of sputum for diagnostic evaluation [71]. The effects of hypertonic saline that aid the clearance of sputum include [39,72,73]:

●Stimulation of a productive cough

●Decreased sputum spinnability (ability to be spun into a strand)

●Decreased sputum viscoelasticity

Despite these effects and the benefits in cystic fibrosis, there is no evidence of any therapeutic value of hypertonic saline aerosols in chronic obstructive pulmonary disease (COPD) [73-75]. In the more specific setting of chronic bronchitis, 7 percent hypertonic saline restored mucus clearance to the normal range [14] but did not improve spirometry or patient outcomes compared with hypotonic control after two weeks [76].

In addition, the administration of either isotonic or hypertonic aerosols can induce a significant decrease in lung function in patients with COPD due to bronchoconstriction [77]. This deleterious effect may be mast cell-mediated, since the decrease in lung function was most pronounced in patients with increased histamine in their sputum. In an eight-week COPD rehabilitation program, with random assignment of 68 patients to either isotonic or hypertonic saline aerosols prior to the exercise sessions, the improvement in six-minute walking distance at conclusion of the program was greater in those receiving isotonic saline, and adverse effects of cough and bronchoconstriction were greater in the hypertonic saline group [78]. Both groups had equivalent improvement in quality of life. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Inhaled airway clearance agents'.)

Oral expectorants — Oral expectorants, such as guaifenesin, bromhexine and its metabolite ambroxol, ipecac, and ammonium salts stimulate the gastric nerve and promote a vagally-mediated increase in airway secretions [10]. As a corollary, all of these agents are actually emetics [79]. Other mechanisms of action may include a reduction in mucus viscosity [10] or an enhancement of the mucociliary elevator [39].

Despite these mucolytic actions, the limited clinical trial data available provide little evidence that oral expectorants improve lung function or subjective well-being in COPD [10,39]. In one study, for example, both bromhexine and guaifenesin improved tracheobronchial clearance but did not change lung function, the frequency of cough, emotional well-being, or the weight and content of sputum [39]. In a 12-month randomized trial (the AMETHIST trial) that included 242 patients with COPD (FEV₁ 60 to 80 percent of predicted), oral ambroxol did not reduce exacerbations of COPD, except in a subgroup of subjects with the most severe symptoms (consisting of cough frequency, expectoration and dyspnea) [80].

Iodide preparations — Iodide acts as a mucolytic by decreasing the viscosity of mucus, facilitating the breakdown of proteins by proteolytic enzymes, and increasing ciliary beat frequency [81]. Iodine preparations include saturated solution of potassium iodide (SSKI), domiodol, and iodopropylidene glycerol. Due to their adverse effect profile, they are not recommended for use as mucolytic agents in COPD.

●SSKI may decrease the viscosity of mucus, but its use is limited by side effects such as a metallic taste, rash, hyperkalemia (in patients with renal insufficiency), and hypothyroidism, particularly if use is prolonged for more than six weeks.

●Domiodol is an organic iodinated mucolytic agent. When administered to tracheostomized patients after laryngectomy, this agent improved cough intensity, sputum quantity and quality, as well as ease of expectoration [82]. It is not available for clinical use.

●Iodopropylidene glycerol has been shown to enhance tracheobronchial clearance and mucociliary transport in expectorating patients with chronic bronchitis [81]. In addition, a randomized, double-blind placebo-controlled study documented improvements in cough, ease of expectoration, and well-being, and a decreased duration of exacerbations [83]. However, in a subsequent randomized, cross-over study, the use of iodinated glycerol for 16 weeks did not improve pulmonary function, wellbeing, or sputum viscoelasticity or clearability [84]. This drug is no longer available in the United States after concerns were raised about carcinogenesis in selected strains of rats and mice.

Sodium cromoglycate — Sodium cromoglycate can improve the depressed tracheal mucus velocity in asthmatics [85]. However, the clinical significance of this finding is uncertain, and sodium cromoglycate has limited availability.

Recombinant human DNase — DNA released by leukocytes is thought to contribute significantly to the viscosity of mucus in patients with cystic fibrosis (CF). Thus, recombinant human DNase is considered a mucokinetic agent that may produce improvement in pulmonary function in patients with clinically stable CF. However, recombinant human DNase does not appear to be effective in the management of non-CF bronchiectasis, and data are lacking regarding its use in COPD. A phase III trial of DNase in hospitalized COPD patients was stopped early because of lack of demonstrable benefit in interim analyses and a trend towards a higher 90-day mortality in the treatment group [86]. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Inhaled airway clearance agents' and "Bronchiectasis in adults: Maintaining lung health", section on 'Mucolytic agents and airway hydration'.)

EXPERIMENTAL MUCOACTIVE AGENTS — Several agents that are mucoactive in the laboratory are being evaluated for clinical use.

Novel mucolytics — A particular disadvantage of current mucolytics is their limited ability to break covalent disulfide bonds. A novel phosphine compound (P3001) is a rapidly-acting reducing agent with lower acid dissociation constant (pKa), higher reduction potential, and increased duration of action compared with N-acetyl cysteine. In in-vitro studies, P3001 decreased MUC5B and spinnability in COPD sputum significantly more than N-acetylcysteine [87]. In small animal transgenic models, P3001 and MUC-031 (another novel thiol-saccharide mucolytic) reduced in vivo airway mucous; MUC-031 also improved mouse survival [87,88].

Surfactant — A surfactant layer is present between layers of mucus gel and periciliary sol fluid, serving to separate these two layers and to facilitate mucus spreading [6,12]. The lubricant properties of surfactant also promote the transfer of energy from beating cilia to mucus [12]. (See 'Properties of mucus' above.)

Several observations suggest a potential role for surfactant as a mucoactive substance, although this use of surfactant remains experimental:

●A decrease in surface-active phospholipid fractions in the sputum of patients with cystic fibrosis (CF; compared with sputum from patients with chronic obstructive pulmonary disease [COPD]) has been found to correlate with increased mucus stasis [89].

●Tracheal instillation of surfactant in anesthetized dogs significantly increases ciliary beat frequency compared to instillation of normal saline [90].

●One randomized, double-blind study of 66 patients with stable chronic bronchitis compared the effectiveness of two weeks of thrice daily, nebulized phosphatidylcholine surfactant (Exosurf) versus placebo [91]. The treatment group had increased in vitro sputum transportability, improvement in pre- and postbronchodilator forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC) by >10 percent, and mildly decreased residual volume (RV)/total lung capacity (TLC) ratios. The high cost of exogenous surfactant precludes its routine use in patients with chronic bronchitis until its salutary effects are better defined in larger trials.

MECHANICAL DEVICES TO IMPROVE MUCUS CLEARANCE — Chest physiotherapy devices, such as oral oscillating devices, high frequency chest wall oscillating devices (HFCWO), external percussion vests, and intrapulmonary percussive ventilation, have been the cornerstone of secretion removal in cystic fibrosis and other forms of bronchorrhea, although data in support of their use in chronic obstructive pulmonary disease (COPD) is limited. We occasionally use oscillating devices (eg, flutter or Acapella devices) for patients with COPD who have tenacious or copious sputum. Patients breathe in and out through the device for several larger than tidal volume breaths and then expectorate any sputum that has been raised.

Several small trials have examined oscillatory devices [92-98]. Systematic reviews of these studies have suggested that use of oscillatory devices may reduce exacerbations (rate ratio 0.50; CI, 0.30-0.83 based on three trials) [99], improve symptom burden (COPD assessment test improvement 6.5 points, 95% CI 5.0-8.1 based on four trials) [99], and increase exercise tolerance (mean difference in six-minute walk distance 50 meters, 95% CI 14-86 based on four trials) [100] in patients with stable moderate to severe COPD, but the quality of the evidence is low to moderate due to incomplete blinding and variability among devices and outcomes.

Devices that achieve airflow oscillation have favorable effects on the viscoelasticity of sputum both in vivo and in vitro and increase mucus movement [101-103].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

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SUMMARY AND RECOMMENDATIONS

●Burden of mucus in COPD – Increased tracheobronchial mucus is associated with increased mortality, an accelerated decline in forced expiratory volume in one second (FEV₁), and an increased risk of hospitalization in COPD. (See 'Introduction' above and 'Properties of mucus' above.)

●Effect of routine therapies – General recommendations for treating excess mucus in COPD focus on the treatment of underlying airways obstruction, airway inflammation, and mucus production by the use of cigarette smoking cessation and guideline-based use of bronchodilator therapy and inhaled glucocorticoids, as well as the occasional use of methylxanthines or phosphodiesterase-4 inhibitors. (See 'Mucoactive effects of routine treatments for COPD' above.)

●Other pharmacologic mucoactive therapies with evidence of benefit

•Short-term and long-term antibiotics – Antibiotic therapy helps in acute exacerbations of COPD associated with increased sputum volume or purulence by reducing the bacterial load that contributes to inflammation and sputum production. In addition, long-term antibiotic therapy may reduce the rate of exacerbations among selected patients who have more than two exacerbations a year. (See 'Antibiotics' above and "COPD exacerbations: Management", section on 'Antiviral and antimicrobial agents'.)

•Thiols and thiol derivatives – We do not routinely use oral thiol preparations in patients with COPD to treat sputum production or to prevent exacerbations. However, for patients with bothersome sputum production that is refractory to smoking cessation, routine therapies for COPD, and a course of antibiotics (when indicated), therapy with an oral thiol preparation (eg, N-acetyl cysteine [NAC], 600 mg twice daily) can be initiated on a trial basis and continued if there is symptomatic improvement. Side effects of thiol preparations include nausea, vomiting, and allergic reactions. We avoid nebulized NAC due to the potential for acute bronchospasm. (See 'Thiols and thiol derivatives' above.)

●Therapies without evidence of benefit – While over-hydration provides no benefit in sputum clearance for patients with COPD, avoiding dehydration is appropriate. Modalities, such as hypertonic saline inhalation, oral expectorants (eg, guaifenesin), oral iodide preparations (eg, saturated solution of potassium iodide [SSKI]), inhaled cromoglycate, and inhalation of DNase, may alter the characteristics of mucus but lack substantial evidence of clinical efficacy. (See 'Mucoactive agents of limited or no benefit' above.)

●Future pharmacologic approaches – Future therapies may include agents that decrease sputum adhesiveness or viscosity and/or decrease sputum production, such as novel mucolytics or surfactants. (See 'Experimental mucoactive agents' above.)

●Use of mechanical devices – Oscillating (eg, flutter valve, acapella device) and other mechanical devices have been used in bronchiectasis to aid in airway clearance. It is not known whether such therapy would be beneficial in patients with COPD. We occasionally use oscillating devices for patients with COPD who have tenacious or copious sputum. (See 'Mechanical devices to improve mucus clearance' above.)