Chronic cough remains a complex clinical entity, in that its symptomatology can vary widely and its underlying mechanisms are not well understood. As such, chronic cough presents special challenges for investigators who seek to understand the multifaceted mechanisms that underlie its clinical presentation, and to find treatments that accordingly address these mechanisms. So far, in this book, the authors have focused on the pathophysiology of cough and the common causes of chronic cough, and have discussed the most relevant treatments as well as the quaternary approach to the complex cough patient. This chapter will focus more on the current translational and clinical research on chronic cough, and novel treatments that are emerging. Some of the concepts are controversial and have not yet been fully developed. However, they form a basis on which current cutting-edge therapies are based.
POTENTIAL UNDERLYING MECHANISMS INVOLVED IN COUGH AND IMPLICATIONS FOR TREATMENT
Potential Mechanisms Underlying Abnormal Glottal Reflexive Responses
Abnormal glottal reflex responses caused by inflammation, viral, mechanical, or chemical factors have long been speculated to underlie mechanisms in chronic cough. Specifically, chronic stimulation of sensory fibers within the larynx are thought to alter laryngeal sensory–motor processes (ie, neuroplasticity) and cause atypical responses for subsequent exposure to typical sensory stimuli.15 However, this hypothesis has largely remained theoretical, with little in the way of empirical studies on this topic. Fortunately, literature from other medical domains could support this mechanistic theory.
One mechanism underlying chronic cough could be the result of local epithelial inflammation. For example, Taramarcaz and colleagues showed epithelial inflammatory damage suggestive of neural changes with picornavirus, a variant of the common cold, in patients with vocal cord dysfunction, which may predispose these patients to a hypersensitive reflexive response in the larynx.16 Studies have also shown increases in subepithelial antigens in laryngeal tissue of infants with hyperreactive supraglottic responses.17, 18
Neuroplastic changes resulting in vagally mediated laryngospasms and apneas secondary to overstimulation of chemoreceptors in the airways have been demonstrated in canine models and infants with exposure to gastric secretions of pH levels less than 2.5.19, 20 Afferent nerves in the respiratory system have been shown to not only stimulate an efferent response to chronic irritation, but to also stimulate a local immune response by recruiting local proinflammatory factors (eg, cytokines). This immune response —known as neurogenic inflammation—causes inflammation and can result in airway remodeling at the peripheral level over time.21, 22
TRPV1 are receptors that cause inflammatory reactions to the airways when exposed to noxious stimuli. Studies by Couto et al and Chandra et al. demonstrated increased activity of TRPV1 in airway tissue with exposure to capsaicin (the active ingredient in hot peppers). TRPV1 have also been shown to increase vascular permeability for calcium and sodium ions responsible for neural conduction, which may explain the increased vagal motor laryngeal reflex response to irritants (eg, capsaicin) in the airways.15, 18, 23, 24 Efferent vagal motor response has been associated with increased muscle contraction, increased breathing rate, and decreased breathing depth,5, 16, 25–27 which may explain why individuals with chronic cough can be triggered with even mild laryngeal irritation and why patients with this condition typically report trouble “catching their breath.”
Cortical Influences in Reflexive Cough Pathways
Van den Bergh and colleagues proposed that chronic cough may have more to do with a Pavlovian-like conditioned response or affective-motivational influences than with direct neuroplastic reflexive changes in the central or peripheral nervous system.28 Put differently, neural connections do much more than sense foreign particulate or irritation at the epithelial or laryngeal level. Behavioral control and information processing mechanisms (eg, associative experiences, perception, attention, emotional processing, and social context) are integrated with these peripheral sensations. The authors suggest the threshold of laryngeal responsiveness may not be to blame, but rather the interaction of sensations and brain behavior mechanisms that result in hyperreactive laryngeal response in patients with chronic cough.28 Additionally, laryngeal nerve stimulation studies indicate that hyperactive motor responses result from central processing of afferent stimuli, rather than from changes in sensitivity or altered receptor distribution within the larynx.20
A possible clinical correlate of this concept may be habitual cough. Often referred to as “psychogenic cough” or “tic cough,” this entity has been described by numerous authors.16–19 While most of the literature focuses on children, adults commonly demonstrate the clinical features as well. Typical history of habitual cough includes a dry, chronic cough characterized by a honking sound and is present throughout the day, but absent at nighttime.29 Although this entity may follow an upper respiratory illness, it is defined as separate from neurogenic cough, the latter of which is believed to be more strictly a disorder of peripheral nerves and brainstem reflexes. Habitual cough remains a controversial entity, as there is no specific proof as to its existence. Despite this, it is important to consider this diagnosis in the evaluation and management of patients with persistent cough despite an otherwise negative workup. Cortical factors likely play a major role in behavioral approaches for the treatment of both neurogenic and psychogenic chronic cough. These behavioral interventions, which are thought to reduce symptoms of cough severity, include cough suppression therapy, speech therapy, mindfulness, meditation, suggestion therapy, biofeedback, and cognitive behavioral therapy.30–32 However, exactly how these approaches interact with cognitive processes require future investigation.
What is currently known of cortical and subcortical influences can be extrapolated from animal studies using retrograde viruses to identify pathways involved in cough and upper airway hyperresponsiveness. Specifically, the sensorimotor cortex becomes active during sensations of increased resistive load, suggesting this area of the brain has direct influences on mechanical stimulation (mechanoreceptors) but not chemical stimulation (chemoreceptors). The insula and cingulate cortex may have more to do with affective processing than discriminative processing of severity of sensations. These two cortical areas are thought to play a role in the perception of unpleasantness of laryngeal irritants by attributing emotion and cognition to the sensory experience.33 This area of the brain may also be where the urge to cough is activated. Future work focusing on these areas of the brain in the context of coughing behaviors should be further explored. Prospective studies comparing actual threshold responses and the effect of emotional influences on laryngeal hyperresponsiveness are also needed to determine the roles neurological, immunological, and psychological factors play in chronic cough.
NOVEL PHARMACOLOGICAL AND SURGICAL TREATMENT APPROACHES
Unlike traditional treatments aimed at symptom control, novel pharmacological and surgical approaches have been proposed to address the elusive intersections of motor and sensory neuropathies that underlie chronic cough symptomology. Neuromodulating agents such as gabapentin, amitriptyline, pregabalin, and baclofen have emerged as first-line treatments for chronic neurogenic cough, with variable but generally favorable results. These agents have been reviewed earlier in this text in Chapter 6, as well as in many systematic reviews in recent years.34–37
A single-patient report of efficacy in treating chronic cough with tramadol was published in 2009.38 Recently, Dion et al published a prospective case series of 16 patients with neurogenic cough who were treated with 50 mg of tramadol every 8 hours as needed.39 Symptoms were assessed using the validated Cough Severity Index (CSI) and Leicester Cough Questionnaire (LCQ) before and after treatment; subjects were included if questionnaires were completed after a minimum of 14 days of treatment. The authors found statistically significant improvement in mean scores following treatment with tramadol. Side effects were minimal, with the most common being somnolence, reported in four out of 16 subjects.39
Glottic Insufficiency and Chronic Cough
Insofar as glottic insufficiency has been proposed as a possible underlying etiology for chronic cough, there have been investigations into the role of vocal fold augmentation to treat chronic cough. Vocal fold augmentation is designed to improve glottal closure through the use of an injectable implant (or filler) or through medialization laryngoplasty (surgical placement of a solid implant within the substance of the vocal folds). Injection augmentation can be performed in the operating room under general anesthesia but is frequently performed in the office setting under local anesthesia. The procedure involves inserting a needle into the vocal folds and using one of several available augmentation fillers. Multiple techniques have been described,40–42 with the goal being to allow the vocal folds to be in full contact during the glottal cycle. Figure 10–1 shows an image before and after injection augmentation.
Crawley et al first described the use of injection augmentation to treat chronic cough in 2015 in a case series of six patients, five of whom reported improvement in CSI scores following injection laryngoplasty to address a diagnosis of chronic cough coupled with vocal fold paresis.43 More recently, Litts et al published a retrospective case series of 23 patients, most of whom (21 out of 23) presented with vocal fold atrophy as the etiology of their glottic insufficiency; the other two had sulcus vocalis or unilateral vocal fold paresis. Fourteen out of the 23 patients underwent behavioral therapy to reduce symptoms. Twenty-one out of the 23 underwent augmentation with Radiesse voice gel, and the remaining two underwent augmentation with Restylane. Nineteen underwent augmentation in the office; the remaining four underwent the procedure in the operating room. Eighteen of 23 patients underwent bilateral augmentation. The CSI was administered before and after treatment. The authors noted a significant reduction in the mean CSI score following injection laryngoplasty. Furthermore, they noted that 11 patients reported a return of symptoms at the 4-month post-injection visit, when the material was thought to have resorbed; eight of these patients went on to proceed with a permanent laryngoplastic procedure.44
Figure 10–1. A. Preaugmentation. B. Postaugmentation.
Botulinum toxin has also been used in an effort to treat chronic cough through injections into the thyroarytenoid muscle. Sipp and colleagues produced one of the earliest reports of Botox injections into the thyroarytenoid muscles in three children with refractory habit cough. The authors described injection of 5 units of botulinum toxin A into each thyroarytenoid muscle under direct laryngoscopy; in each of the three patients, this resulted in cessation of the habit cough, though in one patient the cough resolved immediately following the procedure, well before Botox is known to peak in effect.45
Chu and colleagues described the use of Botox to treat chronic cough in a small case series of four adults. In this series, all patients were reported to have complete resolution of cough after a median of seven injections into the bilateral thyroarytenoid muscles with a mean dose of 4.0 units.46 Subsequently, Sasieta et al published a retrospective case series of 22 patients with chronic cough treated with bilateral Botox-A injections. Treatment success was measured as 50% or greater subjective improvement in cough during a scripted phone call, 2 months after a Botox treatment session. The authors reported that 11 out of the 22 patients (50%) self-reported improvement of 50% or more of cough severity symptoms. Minor complications of transient postprocedural liquid dysphagia and dysphonia were also reported.47
Superior Laryngeal Nerve Block
Efforts to blunt the hypersensitivity of the larynx and to modulate the neurologic feedback loop have further manifested recently in a novel procedure to locally anesthetize the territory of the superior laryngeal nerve (SLN) with a field block. Simpson and colleagues described this procedure in a recent retrospective chart review of 18 patients who underwent SLN nerve block for treatment of chronic cough. The procedure involved an injection of a 50:50 solution of a long-acting particulate steroid and a local anesthetic, delivered via a 27-gauge needle at the entry point of the internal branch of the SLN in the posterior thyrohyoid membrane. Thirteen of the 18 patients included underwent unilateral injections, and five underwent bilateral injections; of the unilateral injections, 10 were left-sided. The patients underwent a mean of 2.4 SLN block procedures, with mean follow-up time following injection of 85.4 days. Outcomes were measured with pre- and posttreatment CSI scores; these scores decreased significantly from mean 26.8 pretreatment to 14.6 posttreatment.48
THINKING OUTSIDE OF THE BOX
Chronic cough as a clinical entity has been acknowledged for more than a century, yet underlying mechanisms are still not well understood. However, the variety of clinical presentations and trigger types suggest mechanisms are likely heterogeneous. Various clinical presentations have been attributed to chronic cough: hoarseness, dyspnea, and globus sensation, to name a few. It is unclear whether these symptoms should be lumped into chronic cough symptomology, whether they fall on a continuum, or whether they reflect common co-occurring yet distinct pathology, such as asthma, paradoxical vocal fold motion disorder (PVFM), and muscle tension dysphonia. Unfortunately, because of the overlap in clinical presentations between chronic cough and other laryngeal- or pulmonary-based pathology, and due to poor understanding of underlying mechanisms driving these clinical expressions, these entities are often lumped together under the same umbrella terms and nomenclature (eg, Irritable Larynx Syndrome). The downside to this approach is that just because symptoms overlap does not mean the underlying mechanisms driving these clinical expressions are the same. Therefore, more focus on the typical role of the larynx and the mechanisms causing dysfunction may be a beneficial approach to guide future investigations and clinical care than grouping these pathologies based on symptoms or triggers.
Various roles of the larynx can be divided into three concepts: airway protection (gatekeeping), ventilatory modulation (respiratory conduit), and communication. Underlying mechanisms involved in these laryngeal tasks are a part of various physiological, neurological, and biomechanical holarchical systems. These systems represent a relationship between entities that are part of a unique identity, but are also made up of subparts and are themselves subparts of a larger whole. The concept of holarchy is different from hierarchy in that the relationships can go “up and down” as well as “side to side.” Conceptually, this can be thought of as multiple sets of nesting dolls with interchangeable parts. For instance, neurological pathways for coughing and breathing both travel and overlap in the nucleus ambiguus in the medulla. However, discharge patterns within the brainstem will rearrange based on upstream cortical input, which leads to distinct laryngeal behaviors, such as coughing and breathing, despite their neurophysiological and structural overlap in the brainstem.2 This may be why patients with spasmodic dysphonia, a local laryngeal dystonia, are able to cough, laugh, and cry, but are unable to use the same laryngeal mechanism for speech.49
When the larynx takes on the role of gatekeeper, it does so to protect the lower respiratory tract. Therefore, it is probably no coincidence the true vocal folds are shelflike, with “down-turned free margins” functioning as a one-way valve.50 The larynx is also smaller in diameter than the trachea and other sublaryngeal structures, which prevents larger particulate matter from entering the conducting airways, although this method of protection is not foolproof, and anything that can get past the larynx inevitably ends up in the (frequently right) bronchi.50, 51 This laryngeal gatekeeping can present as various glottal reflexes (ie, cough, aspiration, swallowing, apneic, and expiratory reflexes), which all involve some combination of vocal fold constriction and a period of apnea.23, 52–55
Specific to cough, the cough reflex is a vagal response to irritants, influenced by chemoreceptors in the supraglottic or glottic region. This reflex prevents inhaled foreign particulates from entering the gas-exchanging area of the lungs. Cough is characterized by a sharp inspiratory phase, a compressive phase, and a short, ballistic expulsive phase.56–59 During a reflexive cough, the true vocal folds, aryepiglottic folds, and oblique/transverse arytenoids act as one to create a single, continuous sphincter, completely closing the laryngeal inlet.60 When the glottis is compressed, intrathoracic pressures increase to 250 to 300 mm Hg. While the abdomen contracts, the glottis opens abruptly to expel about 12 L/s of air (and hopefully the foreign particulate matter with it) through the vocal tract. The intrinsic laryngeal muscle adductors (lateral cricoarytenoids, interarytenoids, and thyroarytenoids) create glottal pressure while the posterior cricoarytenoids (and possibly cricothyroid) activate(s) to quickly abduct the vocal folds for airway clearance. Intercostal and abdominal respiratory muscles contract in conjunction with the glottis during both glottal closure and the expulsive phase.2 When the system becomes hyperreactive or hyperresponsive, these patterns can come in the form of chronic cough or laryngospasm.
In contrast, when the larynx takes on the role of respiratory conduit for ventilatory needs, it tightly couples with the pulmonary musculature to maintain appropriate levels of intrathoracic and intrapulmonary pressure from one cyclical respiratory phase to the next. This is different from the short ballistic patterns involved in cough and other modes of airway protection (eg, deglutition). In respiratory roles, the larynx only closes partially during respiratory tasks to create appropriate levels of subglottal and transglottal pressures as well as intrapulmonary pressures.2, 61 Supralaryngeal structures also help maintain appropriate inspiratory pressures; however, with too much pressure, breathing can become disordered. For example, stenotic nostrils, especially when coupled with an elongated velum, have been shown to produce excessive negative inspiratory pressure above the laryngeal inlet, resulting in eversion of the laryngeal ventricles. This pressure “literally suck[s] the soft ventricular tissue out of its recess and into the laryngeal lumen,” causing stridor and respiratory distress.50
These respiratory laryngeal patterns also become important for different bioenergetic and energy metabolism needs. For example, during prolonged or vigorous activity, respiratory drive increases, and the larynx works in conjunction with the pulmonary system to decrease pulmonary musculature workload and increase ventilatory capability to meet the metabolic needs of the system across respiratory cycles. To accomplish this task, the cross-sectional diameter of the lumen within the larynx increases by way of the arytenoids.50 When discoordination occurs between the upper and lower respiratory tracts, this can result in aberrant vocal fold patterns from one respiratory cycle to the next. One example of these aberrant clinical patterns, commonly referred to as exercise-induced paradoxical vocal fold motion disorder (E-PVFM), involves the vocal folds’ adduction toward the midline, paradoxical of metabolic needs.
Physiological differences between various roles of the larynx for airway protection and ventilation highlight the importance of treating corollary dysfunctions as separate entities (eg, chronic cough and PVFM, respectively). In the former, pulmonary and laryngeal patterns involve acute ballistic neuromuscular activation that results in acute apneic events (ie, cough). In fact, the task of cough temporarily overrides ventilatory needs to protect the airways. In the latter, patterns involve temporal cyclical respiratory dyscoordination leading to dyspnea. Mechanistic differences in physiological patterns and metabolic needs suggest chronic cough and PVFM—at least certain trigger variants like exertion-induced PVFM—are likely discrete entities and should be treated as such when creating study designs in future investigations and planning course of treatment in clinical settings.
Figure 10–2 is a visual representation of a proposed analytical framework to systematically evaluate mechanisms involved in laryngeal behaviors and resultant pathological symptoms. The schematic is by no means comprehensive; the goal is to illustrate the benefit of treating pathology related to the larynx (eg, chronic cough and PVFM) as separate entities. This approach can involve the study of normal physiological mechanisms involved in laryngeal behaviors (respiratory modulation, airway protection, and communication); the influences of structural or anatomical origin (at the supralaryngeal, laryngeal, and sublaryngeal levels); examples of pathological causal mechanisms (white boxes); and resultant pathophysiological symptoms (eg, dyspnea, cough, dysphonia).