2018 Section 6 - Laryngology, Voice Disorders, and Bronchoesophalogy

Airway Hypersensitivity and Cough

March 2016

the distal esophagus via the esophagobronchial re fl ex or activation of sensory nerve receptors in the upper airway, which trigger the afferent loop of the cough re- fl ex. The proposed pathophysiology of airway hyper- sensitivity is abnormal, repeated stimulation of sensory receptors causing neuroplastic changes in brainstem laryngeal controlling networks, inducing them into a perpetually hyperexcitable state, which increases the epithelial sensitivity to sensory stimuli. 10,11 The vocal folds are uniquely exposed to frequent physical stimulation. Phonation involves 100 – 220 Hz adductory vocal fold contact cycles, 12 causing low-grade, repeated stimuli. This rarely incites cough in normal physiologic circumstances, but is increasingly recognized as a trigger for cough in patients with chronic cough patients because of a presumed upregulation of laryngeal sensory receptors. 13,14 In this setting, phonation-induced cough is considered a clinical correlate for upper airway hypersensitivity. Understanding the relative contribution of re fl ux and upper airway hypersensitivity as triggers for chronic cough could help direct therapeutic decisions and improve treatment effectiveness. The aim of this prospective, blin- ded longitudinal study was to explore the relationship between re fl ux, phonation, and cough events over time in a cohort of patients with idiopathic chronic cough using a novel synchronized, continuous recording device. Vanderbilt University Institutional Review Board approved this longitudinal observational trial (IRB #100706). The study population consisted of patients with the chief complaint of chronic cough (duration > 8 weeks) referred to the Digestive Disease Center for evaluation of GERD as a contributing factor and whose chronic cough was refractory to re fl ux treatment. Pa- tients were current nonsmokers with unremarkable chest radiographs who had undergone extensive testing for and exclusion of other common causes of chronic cough (eg, angiotensin receptor inhibitors use, spirom- etry, methacholine challenge), and without voice com- plaints. Excluded were patients < 18 years of age, pregnant, current smokers, had undergone surgery for re fl ux or peptic ulcer disease, or if they had a serious illness that would interfere with study participation. Once consented, patients were excluded if they did not cough or removed their recording monitor during the 24- hour observation period. All acid-suppressive therapies were discontinued at least 10 days before any testing. Methods Patient Population

ambulatory pH-impedance monitoring at least 10 days off acid-suppressive therapy. Encrypted recordings collected by the acoustic monitor device were presence, frequency, and timing of phonation and cough events and time-synchronized pH-impedance data during both up- right and supine states. Patients were instructed to push the symptom bottom in the pH-impedance recorder when they experienced any cough events to temporally compare true cough event occurrence (acoustic recording) with those reported by patients. The entire 24-hour recording for each patient was reviewed by 2 independent study personnel blinded to esophageal pH data to identify, record, and con fi rm all talk and cough event times. Esophageal motility testing and pH- impedance monitoring were performed as previously described. 15 A novel and previously validated acoustic recording system with concurrent time-synchronized 24-hour ambulatory pH-impedance monitoring was used. 15 Cough events were differentiated from throat clearing. Coughs were de fi ned as events having an initial explosive phase involving pre-event inhalation, which contrasts with throat clearing in which no pre-event inhalation occurs. 16 Cough events were detected via phonopneu- mography sensors positioned at 2 sites ( Figure 1 ). 15 An ambient microphone was af fi xed to the patient ’ s shirt collar. Time synchronization of the separate acoustic and re fl ux monitoring recordings was achieved by an elec- tronic signal delivered to both devices to align the signals in time. Study personnel reviewed and recorded all phonation events during the 24-hour study period. Phonation was de fi ned as any talking event occurring in the minute before the cough event. The unit of measurement for analysis was cough events measured repeatedly on the same subject over 24 hours. The repeated measures design provided adequate precision to estimate robust models incorporating time- varying interactions between re fl ux, phonation, and cough in these patients with idiopathic chronic cough. Initial analysis involved dividing each patient ’ s 24-hour observation period into disjoint 2-minute in- tervals. Within each, the presence or absence of phona- tion events, objective pH-impedance, and cough events were identi fi ed and recorded to summarize the total number of 2-minute intervals in which the 8 combina- tions of events did or did not occur. Resultant data provided the probability of coinciding cough, phonation, and pH-impedance events. Symptom index and symptom association probability based on true cough (detected on acoustic monitoring), re fl ux, or phonation events were then independently calculated. Re fl ux, phonation, and Acoustic Monitoring System Statistical Analysis

Protocol and Study Design

Patients underwent 24-hour acoustic recording concurrently and temporally synchronized with

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