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

Tramadol

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

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

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