Therapy for Mucus-Clearance Disorders PDF

Preface

The thought of mucus disturbs many people. Mucus is beneficial as the first defense of the airways. The mucus lining traps inhaled particles and allows them to be cleared from the airway by cilia and cough. The mucus layer also prevents dehydration and desiccation of the airway surface and provides a nutrient milieu for the ciliated epithelium. Mucus can also be quite bad. Airway mucus retention due to hypersecretion or poor mucus clearance is a characteristic of many airway diseases including cystic fibrosis, chronic bronchitis, bronchiectasis, and asthma. Mucus retention is thought to lead to airway obstruction, atelectasis, and tissue destruction by entrapping inflammatory mediators. It promotes microbial retention and growth. The Copenhagen longitudinal study showed that chronic mucus expectoration is associated with a poor prognosis in patients with chronic bronchitis. Mucus is also disgusting, and expectoration of sputum is often associated with lack of refinement and the spread of disease. It has even been postulated that, because of the social stigma associated with expectorating, persons who voluntary suppress cough and sputum expectoration are more likely to develop airway damage; this is called Lady Windemere' s syndrome.

It is far to say that mucus is complex. Neither an ideal liquid nor a solid, mucus is a viscoelastic gel secreted by several different cell types and cleared from the airway by different mechanisms. Mucus is difficult to collect and a challenge to analyze. Because of this, mucus has proven fascinating to physicians, physical therapists, and physiologists, to pharmaceutical and biotechnology companies, and to epidemiologists and 8-year-old boys. There is now a critical group of investigators around the world studying many aspects of mucus secretion and clearance, and we are fortunate that many of these "phlegmish masters" have contributed their knowledge to this art book.

The book opens with an overview of airway mucus clearance by Duncan Rogers. This is an important review of the physiology and pharmacology of mucus secretion and clearance. Malcolm King then discusses methods for measuring mucus viscoelasticity and gives a practical underpinning for the use of mucolytic agents. Dr. King also explains the complex polymer chemistry involved in the biophysical evaluation of mucus properties. Dr. Jonathan Widdicombe follows this with a chapter on the regulation of mucus secretion describing how mucus secretion and clearance are coordinately regulated. He explains the mechanisms of mucus hypersecretion in persons with chronic airway inflammation and briefly discusses interventions that may reduce hypersecretion.

Medications to promote sputum clearance are sold without prescription around the world and represent a large share of the over-the-counter drug market, but proof of efficacy is very limited. One of the challenges facing those who develop, evaluate, and market mucus-clearance therapies is deciding on appropriate and meaningful outcome variables for clinical trials. In Chapter 4, the various efficacy measures that have been used are critically reviewed and specific recommendations given for choosing outcomes that are appropriate for the medication or device and for the patient population being studied. Because airway-clearance techniques can be effort- and time-intensive-especially when used several times daily for months and years, Dr. Webb and colleagues describe the results of studies evaluating adherance with common airway-clearance techniques, offering suggestions for improving adherance to therapy. These two chapters along with the final chapter in Part Two, by Dr. Babatunde Otulana and colleagues, provide useful guidelines for those interested in drug and devices development and clinical evaluation. Dr. Otulana has spent many years at the U.S. Food and Drug Administration and in industry. From this perspective he gives clear guidance on regulatory issues related to the development of drugs and airway-clearance devices.

Part Two discusses mucoactive medications. Many classification systems have been used to describe mucoactive medications. Chapter 6 provides a classification based on their putative mechanism of action. This chapter is also an overview of subsequent chapters discussing these different medications. Because mucoactive medications can be delivered orally, parenterally, or by therapeutic aerosol, Drs. Amirav and Newhouse review the advantages and disadvantages of each of these routes and discuss techniques for aerosol delivery in detail.

Expectorant medications increase the volume and water content of airway secretions. This is the class of mucoactive medication that has been in longest use, going back to ancient therapies for pulmonary diseases. Dr. Ziment reviews this fascinating history and provides an evidence-based assessment of the potential effectiveness of these medications.

Mucolytics are medications that specifically reduce the viscosity of mucus secretions by disrupting or disentangling the polymer structure of mucus. Classic mucolytics do this by virtue of effects on mucin polymers while peptide mucolytics disrupt the pathological DNA and actin polymers in sputum. Dr. King presents the molecular basis for mucolytic therapy.

Mucus is first cleared by coordinated ciliary activity. Drs. Rutland, Morgan, and de Iongh explain the physiology of mucociliary clearance and the contribution of ciliary beat force, beat frequency, and beat coordination (metachronicity) in this process. They describe primary and secondary disorders of ciliary activity and structure and how medications can affect mucociliary clearance.

Mucokinetic medications increase the cough transportability of sputum, usually by increasing expiratory air flow or by reducing the adhesion of mucus to epithelium. Surfactant phospholipids are the best described of the mucokinetic agents. Drs. Anzueto and Rubin describe the balanced processes of mucusepithelium adhesion and abhesion and how abhesive medications like surfactant can improve mucus and sputum clearance in persons with chronic hypersecretory airway diseases associated with epithelial damage.

Mucoregulation is the process of decreasing chronic mucus hypersecretion that can obstruct and damage the airway. Dr. Tamaoki and colleagues explain the presumed mechanism of action of these agents and describe the clinical use of each of these types of medication, with special emphasis on the glucocorticosteroids and the macrolide antibiotics.

Hyperosmolar aerosol inhalation has been used both for sputum induction and to promote sputum clearance in persons with cystic fibrosis or bronchiectasis. Like ion-channel modifiers that increase the transport of ions (primarily sodium and chloride) and water into the airway lumen, hyperosmolar aerosols have been shown to increase mucus secretion, decrease sputum adhesion to the epithelium, and perhaps "thin" mucus by increasing airway water transport. Dr. Kishioka describes the physiology of ion and water transport in the airway and reviews the clinical use of this class of mucoactive medications.

Although mucoactive medications have primarily been used to treat pulmonary disease, the upper airway, including the paranasal sinuses and the eustachian tubes, are also mucus secretion ciliated epithelia. Otolaryngologists, allergists, and rhinologists have long recognized that sinus mucostasis can lead to recurrent bacterial infection and chronic sinusitis and otitis media. Professors Sakakura and his colleagues explore the use of mucoactive therapy for upper-airway disorders and give practical suggestions for using and assessing these therapies.

Chapters 16 and 17 then review the application of chest physical therapy and breathing techniques as physical means to enhance mucus clearance. The various airway-clearance device modalities are described in detail, as well as the physiology of mucus clearance by the application of physical therapy, with specific recommendations given for both. The term chest physical therapy usually suggests the application of various breathing techniques, hand clapping on the chest, and vibration and postural draining, all to promote more effective cough and sputum expectoration. Dr. Olseni and colleagues discuss the proposed mechanism of action for these maneuvers, the evidence for their effectiveness, and their common use to promote mucus clearance.

A variety of devices have been developed and tested that are meant to improve mucus clearance by altering the physical interaction of the secretions with the epithelium. High-frequency oscillation, positive expiratory pressure, and Flutter are thought to help secure airway patency and enhance expiratory airflow while helping to detach secretions bound to the airway wall. Mr. Fink and Dr. King differentiate these techniques and give evidence-based suggestions for their clinical application.

Chapter 18-20 describe special consideration related to airway-clearance techniques and medications for children, patients in the perioperative period, and those with neuromuscular disease. These are patient populations with special needs and requirements that are well described by the authors.

The child with acute or chronic difficulty with mucus clearance presents a special set of problems for the therapist. Children can have difficulty with the independent performace of physical therapy or breathing techniques and the youngest children (generally those less than 5 years of age) will rarely expectorate sputum even when coughing. Professor Zach and Dr Oberwaldner review the theraputic considerations in treating children and how these can be modified to be most effective at different ages.

Postoperative patients are at greater risk for mucostasis, atelectasis, and pneumonia because of immobility, pain, weakness, and any residual effects of anesthesia. Chapter 19 discusses the special risk posed by surgery and how to best prevent and treat mucostasis in the perioperative period.

Patients with neuromuscular diseases such as spinal motor atrophy, amyotrophic lateral sclerosis, or muscular dystrophy frequently develop chest infections from secretion aspiration and from poor cough due to muscle weakness. Dr. Bach cares for a large number of patients with neuromuscular disease and he has developed and tested specific and effective protocols and procedures to enhance mucus clearance and prevent atelectasis and infection.

The study of mucus secretions and clearance in health and disease is a rapidly evolving field. This has been one of the most difficult-to-treat components of asthma, cystic fibrosis, chronic bronchitis, and other chronic inflammatory airway disease, but appropriate therapies promises some of the greatest benefits in these diseases. This book gives an in-depth evaluation of the physiology of airway mucus secretion and clearance as well as medications and devices used to clear mucus from the lungs. It also provides specific guidelines for development and testing of new therapies.