Mucolytic Therapy: What,When,Where,Why,and What Is the Evidence?

Introduction

Mucociliary clearance is the primary defense against infections and particulate irritants in the lung. However, chronic inflammatory airway diseases such as asthma, cystic fibrosis, chronic bronchitis, and bronchiectasis are associated with impaired mucociliary clearance, further contributing to ongoing infection and loss of lung function. Recent extensive reviews of the physiology, genetics, pathophysiology of mucus, and use of mucoactive agents have been published.^1–3 Here we will briefly review the clinical evidence for efficacy of mucolytic agents in pediatric airway disease. Mucus lines the epithelial surface of the airways in a bi-layer of gel on top a sol phase with a thin layer of surfactant in between. ¹ The gel is primarily made up of a class of high-molecular-weight glycoproteins called mucins produced by epithelial goblet cells. ¹ Serous cells and other epithelial cells maintain the sol layer. Mucus requires a balance between viscosity primarily from the sol layer and elasticity, a property of mucins, for the epithelial cilia to work properly to clear mucus. ¹ During infection, inflammation, and mucus hypersecretory states, there is an increase in not only mucin secretion but also the addition of DNA, filamentous actin, and proteoglycans from the breakdown of inflammatory cells as well bacteria and bacterial biofilms that combine with mucin to produce sputum.^2,3 Of interest is that high viscosity improves cough clearance but decreases normal ciliary clearance, and loss of elasticity decreases normal ciliary clearance.^2,3 Thus, liquefying sputum will not necessarily improve mucociliary clearance in all instances, and differing approaches for different diseases are now being explored. ³ Mucolytics by definition are those agents that thin mucous secretions, reducing the viscosity of mucus.

N-Acetylcysteine

N-acetylcysteine, one of the first clinically used mucolytics, is a thiol compound with free sulfydryl groups that when aerosolized dissociate mucin disulfide bonds, reducing viscosity and elasticity of mucus. Although it has well-established mucolytic activity in vitro and reduces viscosity of mucus acutely when administered to a variety of patients with airways disease, N-acetylcysteine has not been shown to be particularly effective on a long-term basis either for improving lung function, dyspnea, or cough in chronic bronchitis or improving lung function and other outcomes in cystic fibrosis.^4,5 Aerosolized N-acetylcysteine is poorly tolerated, producing nausea and stomatitis as well as inducing bronchospasm in asthmatics. As a result of the side effects from aerosol administration, oral administration of N-acetylcysteine has been investigated as a mucolytic and for its possible antioxidant effects. ³ Despite some early trials suggesting significant reductions in exacerbations in chronic bronchitis, ⁶ a large 3-year multicenter clinical trial of 600-mg daily N-acetylcysteine orally versus placebo failed to show an improvement in annual decline in forced expiratory volume in 1 s (FEV₁) or a reduction in exacerbations. ⁷ A recent Cochrane Review, however, suggested that oral mucolytics may be of benefit in reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD), particularly those who experience frequent prolonged exacerbations. ⁸ However, this review included all oral mucolytics and not just N-acetylcysteine, and there was a great deal of heterogeneity between studies. A Cochrane Review of oral thiol derivatives found no benefit for these agents in cystic fibrosis. ⁹

Dornase Alpha

Recombinant human DNase or dornase alpha was developed because of the finding that much of the tenacious sputum in patients with cystic fibrosis contained not increased mucin but large amounts DNA strands from leukocytes and other cells.^2,3 The most recent publication of the Pulmonary Therapies Committee of the Cystic Fibrosis Foundation strongly recommends the chronic use of dornase alpha for patients 6 years and older with moderate to severe lung disease. ⁵ There is substantial evidence that dornase alpha improves lung function and some evidence that it reduces exacerbations in these patients. ⁵ The most recent Cochrane Review supports this recommendation. ¹⁰ However, only one study each reported improved lung function at 1 year ¹¹ (n = 72) and 2 years ¹² (n = 410); thus, the issues concerning long-term administration still exist: how long is long-term and is alternate day use as effective as daily use?^5,13 For cystic fibrosis patients with mild lung disease (FEV₁ 70%–90% predicted) the Pulmonary Therapies Committee recommendations for dornase alpha are not as strong with an evidence ranking of B, but they still recommend chronic use. This was primarily based upon the results of 1 double-blind placebo-controlled study in children 6–10 years old (N = 474) with forced vital capacities ≥85% predicted. ¹² They reported a 3.2% improvement in FEV₁ and 34% reduction in risk of exacerbations from dornase alpha.

The Committee also included the results from 2 preliminary pilot studies in children <5 years in their analysis and recommendation.^5,14,15 One included only 9 infants (0.7–1.9 years old) in a 2-week open-label crossover comparison with normal saline. ¹⁴ The investigators utilized a rapid thoracic compression and body plethysmography to assess airflow and reported improved airflow during and after the dornase alpha but not the normal saline for 2 weeks. There was no significant difference in symptoms or overnight oxygen saturations. The other study was a 100-day double-blind placebo-controlled parallel study in 12 children 1.1–4.9 years old primarily designed to determine if high-resolution computerized tomography scans could detect differences in therapy. ¹⁵ The authors reported a significant improvement in high-resolution computerized tomography scores but not chest radiograph scores in the dornase alpha group compared to placebo and nonsignificant differences in parent report of improvement. Thus, the use of dornase alpha in children <5 years of age awaits evidence of further efficacy before it can be recommended. ¹⁶

Dornase alpha has been used in atelectasis in infants and children and studied in acute asthma and bronchiolitis in children. The reports of use in atelectasis are open label case series and thus do not constitute evidence of efficacy.^17,18 A single dose of dornase alpha did not improve outcomes in acute severe asthma in the emergency department, ¹⁹ and a well-done trial in 225 infants with oxygen-dependent bronchiolitis dornase alpha administered twice daily during the hospitalization did not alter any outcome. ²⁰ Dornase alpha has also been studied in adults with idiopathic bronchiectasis.^21,22 A 14-day trial failed to show an improvement in lung function or an improvement in sputum transportability, ²¹ and a large 24-week multicenter trial reported that patients receiving dornase alpha had greater declines in FEV₁ and more exacerbations. ²² Thus, outside of its efficacy in cystic fibrosis, dornase alpha has not demonstrated efficacy in other pulmonary diseases.

Hyperosmolar Agents

Current hyperosmolar agents include hypertonic saline and mannitol, but they were initially investigated in late 1960s and 1970s, when urea was found to decrease viscosity of mucus in vitro obtained from patients with cystic fibrosis and bronchiectasis. ²³ A preliminary clinical study demonstrated improved sputum volume and viscosity when aerosolized to patients with COPD, bronchiectasis, and cystic fibrosis without significant adverse effects. However, follow-up studies in patients with asthma demonstrated significant reductions in FEV₁ following urea aerosolization discouraging further interest as a mucolytic.^24,25 Hypertonic saline was first shown to enhance mucociliary clearance and increase sputum volume in patients with chronic obstructive pulmonary disease, ²⁶ but because it also produces an acute decline in FEV₁ in patients with asthma it has been primarily used in combination with bronchodilators as a mucolytic/expectorant for induced sputum studies in asthma to identify inflammatory biomarkers. ²⁷ More recently, hypertonic saline and mannitol have been used increasingly as indirect airway challenges to help diagnose asthma and exercise-induced asthma, as the mechanisms for bronchospasm in asthma following hyperosmolar challenges have been better defined. ²⁸ The U.S. Food and Drug Administration recently approved a dry-powder preparation of mannitol as a bronchoprovocation test in asthma and it is currently undergoing clinical trials as a mucolytic in cystic fibrosis and bronchiectasis.^29,30 Hyperosmolar agents presumably work by enhancing dispersion of mucus gel and increasing the volume of periciliary fluid by drawing water into the airways.^1–3

The Pulmonary Therapies Committee of the Cystic Fibrosis Foundation recommends the use of hypertonic saline (6%–7%) chronically in patients 6 years and older to improve lung function and reduce exacerbations. ⁵ However, evidence was only considered fair and given a grade of B. Two studies have compared 3% and 7% saline and both indicated greater improvement in FEV₁ 2–4 weeks from 7% saline. ³¹ The most recent Cochrane Review of hypertonic saline generally supports the use of hypertonic saline for cystic fibrosis for improving lung function and reducing exacerbations. ³¹ However, the long-term use is still in question as the only study going out 48 weeks did not find an significant improvement at that time over placebo for improvement in FEV₁. ³² That study did find a significant reduction in exacerbations over that time period. Direct comparisons with dornase alpha have been few but tend to show greater improvement in lung function for dornase alpha.^13,31 This raises the issue of whether or not hypertonic saline is additive to dornase alpha. While the additive benefit has not been directly assessed, 36% of the patients in the 48-week study of hypertonic saline compared to placebo were receiving dornase alpha and post hoc analysis showed that its presence did not alter the outcome. ³² One small preliminary investigation of hypertonic saline in bronchiectasis reported greater production of sputum following 7% saline plus terbutaline than following terbutaline alone. ³⁰

Mannitol 420 mg dry powder twice daily for 2 weeks improved FEV₁ a mean of 7% from baseline in a preliminary phase 2 trial in 39 patients with cystic fibrosis without airways hyperresponsiveness. ³³ Forty-six percent of the patients were receiving dornase alpha that did not appear to alter the results. Twenty-eight children with cystic fibrosis and negative airway hyperresponsiveness were randomized to an open comparison of three 12-week treatments with mannitol, dornase alpha, and the combination. ²⁹ Mannitol and dornase alpha produced similar improvement in FEV₁ but the combination of dornase alpha and mannitol did not, suggesting that the combination was not useful. However, these 2 initial trials were preliminary investigations, and larger multicenter trials will be needed before any conclusions can be drawn. Similarly, some preliminary trials in bronchiectasis show that single doses of mannitol enhance mucus clearance, but there is still insufficient data to support its use.^30,34

Conclusion

Dornase alpha has well-established short-term and long-term benefit in cystic fibrosis but not other pulmonary diseases. Hypertonic saline is established as improving mucociliary clearance in cystic fibrosis, chronic obstructive pulmonary disease, and bronchiectasis but has only modest efficacy for improving clinical endpoints (ie, lung function and exacerbations) for cystic fibrosis in the short-term and some efficacy for clinical endpoints (1 study) in the long-term. Hypertonic saline has no established efficacy data for clinical endpoints in bronchiectasis. Mannitol has demonstrated improved mucociliary clearance in cystic fibrosis and bronchiectasis and preliminary evidence of clinical efficacy in cystic fibrosis but cannot be recommended at this time. In contrast, the first of the mucolytics, N-acetylcysteine, has failed to establish clinical efficacy in any pulmonary diseases.