Mucus Hypersecretion

Mucus has many functions within the respiratory tract including regulation of the immune response and cell differentiation; maintenance of respiratory tract hydration; and creating a barrier defense against particulate matter, including pathogens.14 Mucins comprise a significant portion of airway mucus and contribute to the barrier function of mucus. There are more than 20 mucins in the human lung.15 The major airway mucins: MUC1, MUC4, MUC5AC, MUC5B, and MUC16.15 MUC1, MUC4, and MUC16 are membrane-tethered and MUC5AC and MUC5B are secreted by goblet cells and submucosal glands, respectively.15 Respiratory mucus also contains several other substances secreted by epithelial cells with inhibitory activity against inhaled pathogens including lysozymes, lactoferrin, proteases, protease inhibitors, nitric oxide, and hydrogen peroxide.15

The interaction between flu viruses and mucins was first identified over 70 years ago.16 Numerous in-vitro and animal studies have since confirmed that mucins play an integrated role in the host response to pathogens, both before and during the immune response.15 The cilia of the upper respiratory mucosa is responsible for transporting mucus out of the nasopharynx. In Sakura’s investigation into the relationship between mucociliary function and acute upper respiratory tract infection, marked and long-lasting impairment of nasal mucociliary transport rate and clearance in the nose was found.17,18 This was attributed to a combination of damage to the ciliated system, a change in the flow properties of nasal secretions, and other in vivo factors, all leading to increases in the volume of nasal secretions and pooling of virus-laden secretions in the nasopharynx.19-21

Treatment of Mucus Hypersecretion

The inability to clear mucus is a major contributor to discomfort. Aside from antivirals, which only reduce the duration of influenza, treatment is largely focused on symptoms. Patients with colds and influenza frequently turn to over-the-counter (OTC) medications to relieve their cough and congestion symptoms.4 Nurse practitioners (NPs) and PAs are in an ideal position to guide patients to the most appropriate OTC treatments based on their most bothersome symptoms, pre-existing medical conditions, and current medications. They can also provide guidance about the different classes of OTC mucoactive drugs (ie, those that alter either the viscoelastic properties and/or promote secretion or expulsion of mucus). Mucoactive medications include expectorants, mucoregulators, mucolytics, and mucokinetics (Table 2).22


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Table 2. OTC Mucoactive Drugs and Their Potential Mechanisms of Actiona

Class/AgentPotential mechanism of action
Expectorants 
• GuaifenesinStimulates secretion and reduces mucus viscosity
Mucoregulators 
Anticholinergic agents
• Brompheniramine
• Cetirizine
• Chlorpheniramine
• Clemastine fumarate
• Diphenhydramine
• Fexofenadine
• Loratidine
• Promethazine
Decrease secretion volume
Glucocorticoids
• Fluticasone propionate
• Triamcinolone acetonide
Reduce airway inflammation and mucin secretion
Mucokinetics 
Bronchodilators
• Ephedrine
Improve cough clearance by increasing expiratory flow
aTable lists commonly used agents and is not a comprehensive list of all currently available agents. bavailable only as a prescription nebulizer solution.
Adapted from Balsamo et al.22

Globally, over 50 mucoactive compounds are available; in the United States, the Food and Drug Administration (FDA) has approved only 2 for this purpose: guaifenesin, an expectorant; and N-acetylcysteine, a mucolytic.

Expectorants target mechanisms that promote increased mucus hydration and clearance from the respiratory tract by making coughs more productive and reducing cough reflex sensitivity.23 The only FDA-approved OTC expectorant is guaifenesin, which is thought to work by reducing the viscosity of secretions in the trachea and bronchi as well as stimulating the flow of respiratory tract secretions, allowing ciliary movement to carry the loosened secretions toward the pharynx.24 The precise mechanism by which expectorants exert their action is unclear, although they may act as irritants to gastric vagal receptors, and recruit efferent parasympathetic reflexes that induce glandular exocytosis of a less viscous mucus mixture.25

It has been suggested that expectorants may have a role as a prophylactic agent in the fight against COVID-19.26 Similar benefits may be seen in treatment of mild cases of COVID-19; however, studies are currently lacking.

A number of studies have evaluated the efficacy of guaifenesin in ARI. A large placebo-controlled pilot study in 378 patients with ARI and productive cough explored subjective patient-reported outcome measures such as severity of chest congestion, mucus thickness, and cough. Some of these parameters showed strong trends or statistically significant differences in efficacy between guaifenesin and placebo; the most significant symptom improvements were seen with cough and symptoms associated with excess and tenacious mucus.27

Guaifenesin has a well-established safety profile supported by data from numerous published clinical studies and over 50 years of post-marketing surveillance.28 In a continuous safety surveillance analysis of 8 common cough and cold drugs conducted from 2008 through 2014, guaifenesin showed the lowest number of at least potentially related nonfatal adverse event cases (1%) out of a total of 5610 index drug reports.29

Mucoregulatory agents exert their effect by modifying mucus secretion. This class includes anticholinergics and glucocorticoids, although none have been approved specifically for the treatment of colds or influenza.

Carbocysteine and N-acetylcysteine (NAC) are both mucolytic agents, however, only NAC is approved for use in the US. In vitro studies have demonstrated that NAC breaks disulfide bridges between the macromolecules present in mucus leading to reduced mucus viscosity. It has been used clinically for over 30 years in the management of respiratory disease. N-acetylcysteine is not available OTC and reports of respiratory bronchorrhea and acute respiratory distress in pediatric patients while receiving these treatments for respiratory tract infections led to withdrawal of their licenses for infants in France and Italy.30 Additionally, 2 case reports suggest that carbocysteine may cause pneumonia in predisposed patients.31,32

Patient Education on Flu Vaccination

Office visits for cold and flu may be one of the best opportunities providers have to provide personalized education for patients on appropriate and safe treatments as well as encourage flu and COVID-19 vaccination. The Centers for Disease Control and Prevention offers recommendations for patient education on influenza and COVID-19 vaccines.

Discussion

Clinicians play a key role in patient education on the risks and benefits of over the counter medications for treatment of mucus hypersecretion resulting from colds and influenza. Unlike many other OTC cough and cold medications that contain dextromethorphan and pseudoephedrine, guaifenesin is not associated with serious side effects or abuse/dependence problems.34-36 Given its favorable benefit/risk profile, guaifenesin appears to be a useful agent to recommend to patients with cold and influenza symptoms.

Kami Whitney, MPAS, PA-C, is an Internal Medicine provider at Arjun Medical Center in Gainesville, VA.

Reference to specific commercial products, manufacturers, companies, or trademarks does not constitute its endorsement or recommendation by the US Government, Department of Health and Human Services, or CDC.

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