Laryngeal Vibrotactile Stimulation Is Feasible, Acceptable To People With Unexplained Chronic Cough

Abstract

Objectives:

Unexplained chronic cough (UCC) is common and has significant impacts on quality of life. Ongoing cough can sensitize the larynx, increasing the urge to cough, and perpetuating the cycle of chronic cough. Vibrotactile stimulation (VTS) of the larynx is a non-invasive stimulation technique that can modulate laryngeal somatosensory and motor activity. Study objectives were to assess feasibility and acceptability of VTS use by people with UCC. Secondarily, changes in cough-related quality of life measures were assessed.

Methods:

Adults with UCC recorded cough measures at baseline and after completing 2 weeks of daily VTS. Feasibility and acceptability were assessed through participant-reported device use and structured feedback. Cough-related quality of life measures were the Leicester Cough Questionnaire (LCQ) and the Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ).

Results:

Nineteen adults participated, with mean age 67 years and cough duration 130 months. 93% of planned VTS sessions were logged, 94% of participants found the device comfortable to wear, 89% found it easy to operate and 79% would recommend it to others. Pre-post LCQ change achieved a minimal important difference (mean 1.3 (SD 2.4, p=0.015)). NLHQ scores improved, but did not reach a minimal important difference.

Conclusions:

Laryngeal VTS use was feasible and acceptable for use by patients with UCC, and was associated with a meaningful improvement in cough-related quality of life. Future studies will include VTS dose refinement and the inclusion of a comparison arm to further assess the potential for laryngeal VTS as a novel treatment modality for UCC.

Graphical Abstract

This study examined the feasibility and acceptability of laryngeal vibrotactile stimulation (VTS) in people with unexplained chronic cough. Laryngeal VTS use was feasible and acceptable, and was associated with modest improvements in cough-related scales. Future studies will further examine laryngeal VTS use for chronic cough.

Introduction

Cough is one of the most common reasons for patients to seek medical care.¹ In 2% to 18% of the global adult population, cough persists for >8 weeks² and can result in the need for specialty care. Chronic cough can significantly reduce quality of life³ by causing exhaustion, worry, embarrassment, trouble with speaking, limiting occupational and social interactions, and depression.⁴ A significant proportion of chronic cough persists despite disease-specific treatments such as for asthma, reflux, and allergies.⁵ Such unexplained chronic cough (UCC) has been conceptualized as a cough hypersensitivity syndrome.

Cough hypersensitivity syndrome is characterized as a hyperreactivity of the upper respiratory tract that leads to intense, disruptive coughing fits in response to minor stimuli.^6,7 This cycle is perpetuated in patients with this condition as the coughing itself further irritates the larynx, leading to increased laryngeal sensitization and an increased urge to cough. This syndrome is conceptualized as a neuropathic problem, in which the peripheral and central response to minor stimuli (such as talking or temperature changes) is excessive. Specifically, it is thought that there is a decreased ability to suppress cough when compared to healthy controls.⁸ This is also supported by the recent finding that laryngeal somatosensory-motor cortex activity does not show normal phonation-related suppression in people with UCC.⁹ Thus some patients are treated with neuromodulating medications such as gabapentin and pregabalin,^10–12 but systemic side effects can be barriers to use.

The larynx is arguably the anatomic epicenter of cough. The larynx plays a major sensory afferent role in cough by detecting the presence of noxious or particulate substances that should be ejected from the respiratory tract via cough, and also plays an important motor role in cough since precisely timed vocal fold adduction is necessary to build up enough subglottic pressure to generate an effective cough. Thus the larynx is a logical target for treatment. While superior laryngeal nerve blocks are helpful for some patients with chronic cough,¹³ the procedure is invasive and may have to be repeated. Behavioral cough suppression therapy can be helpful,¹⁴ but not all patients benefit, and access to specialty care can be a barrier. Thus additional therapeutic approaches may be helpful to explore.

In laryngeal dystonia, vibrotactile stimulation (VTS) to the larynx has been shown to alter laryngeal motor activity and laryngeal somatosensory cortical activity.¹⁵ Laryngeal VTS has been well-tolerated in patients with laryngeal dystonia, with reduction of laryngeal spasms and associated improvements in voice quality.¹⁵ Importantly, there appears to be no negative impact on swallow function.¹⁶ Because people with UCC may present with abnormal activity in the same regions of laryngeal somatosensory cortex⁹ as people with laryngeal dystonia,¹⁷ and laryngeal VTS can be effective in laryngeal dystonia,¹⁵ a logical next step is to evaluate the potential use of laryngeal VTS in people with unexplained chronic cough.

Thus, the objectives of this study were the following: (1) assess the feasibility and acceptability of laryngeal VTS in people with UCC and (2) measure the change in Leicester Cough Questionnaire (LCQ)¹⁸ associated with VTS use. As a secondary patient-reported outcome measure, Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ)¹⁹ scores were also examined.

Although it was conceivable that laryngeal VTS might exacerbate throat irritation in people with UCC, given good tolerance in other patient populations we hypothesized that laryngeal VTS would be feasible and acceptable to people with UCC. We also hypothesized that we would observe a minimal important difference reduction on the LCQ and NLHQ associated with the application of laryngeal VTS.

Methods

Participants

All participants completed written informed consent prior to participation. Ten participants were recruited from academic and private otolaryngology, pulmonary, and gastroenterology clinics, and nine volunteered to participate through the University of Minnesota’s Study Finder website. The study protocols were approved by the institutional review board of the University of Minnesota (STUDY00012174) and the study was registered at clinicaltrials.gov (NCT05273190).

Inclusion criteria included age 18–88 years, presence of an unexplained cough for 8 weeks or longer (with “unexplained” considered to include negative chest imaging obtained as part of evaluation for the cough; no current use of ACE-inhibitors; no current acute upper respiratory infection; no history of neuromuscular impairment that may affect cough/laryngeal sensation and/or function (e.g., multiple system atrophy, Parkinson disease, cerebrovascular accident); no history of aspiration pneumonia; no smoking within the past three months; judgment of their medical providers that an untreated or inadequately treated gastroesophageal, pulmonary, and/or sinonasal source was not the primary cough etiology; cough visual analogue scale (VAS) rating of 30 or greater on a 0–100 cough severity scale;²⁰ ability to complete questionnaires in English, and ability to provide informed consent.

Exclusion criteria included factors that might contraindicate laryngeal VTS use (recent intubation or neck surgery, presence of electronic implants (e.g., neurostimulator or pacemaker), body mass index greater than 40), and evolving or concurrent treatments that could affect cough (eg, titration of neuromodulating medication, speech therapy).

Device

The laryngeal vibration device used is described in detail in previous work.¹⁵ Briefly, two vibromotors (Model 307–100, Pico Vibe, Precision Microdrives Ltd., London, UK; diameter: 8.8. mm, length 25 mm) were positioned over the bilateral thyroid laminae and fixated with hypoallergenic tape. The vibration frequency was set at 100Hz. Previous work determined that a vibration frequency of 100 Hz at the skin results in 60–70 Hz vibration at the larynx,¹⁵ which is within the frequency range known to stimulate laryngeal mechanoreceptors.²¹

Measures

Feasibility and acceptability. Feedback on the use of the VTS device was collected through a structured survey at the time of the final assessment. Participants were asked to log each time they started and completed a VTS use session. Patients also responded to statements about the usability of the VTS device, including: it was comfortable to wear, easy to operate, and I would encourage a friend with a similar problem to try it, using a 5 point Likert Scale (strongly agree, agree, not sure, disagree, strongly disagree). Responses of agree and strongly agree were considered to be in support of the presented statements.

Patient-reported outcome measures. The Leicester cough questionnaire (LCQ)¹⁸ was designated as the primary patient-reported outcome measure. It is a 19 item questionnaire that assesses aspects of cough related quality of life. The LCQ is a well-established patient-reported cough outcome measure that has been validated for use in patients with UCC.²² It includes physical, psychological and social domains and the average of the domain scores determines the overall LCQ. A minimal important difference (MID) in the total score has been defined as 1.3 on this scale,²³ which is helpful for interpretation of the efficacy and impact of chronic cough treatments on cough-related quality of life. The secondary patient-reported outcome measure was the Newcastle Laryngeal Hypersensitivity Questionnaire (NLHQ),¹⁹ a 14 item questionnaire that assesses aspects of laryngeal sensatiation related to chronic cough. The NLHQ includes three domains: obstruction, pain/thermal, and irritation. A MID on the NLHQ total score has been defined as 1.75.¹⁹

Study structure

Participants completed an assessment at baseline that included relevant sociodemographics as well as the LCQ and NLHQ. They were instructed as to how to place the VTS stimulators and how to operate the VTS device. They then used the VTS device for 20 minutes once per day for 2 weeks, based on a prior protocol of VTS use in laryngeal dystonia,¹⁵ and logged each use session via the secure and HIPAA-compliant REDCap web portal. Immediately following completion of the 2 weeks of VTS use, they completed usability questions as well as the LCQ and NLHQ.

Analyses

Statistical analysis was performed in R [R 4.3.1]. Descriptive statistical analyses were performed, followed by one-sided paired t-tests comparing baseline and final scores after confirming normality using the Shapiro-Wilk test.²⁴ For missing items of scales that were ≥80% complete, mean imputation was performed across all completed items for a given scale. This cutoff was predetermined. No participants had <80% complete scales. Because multiple comparisons were made (pre vs post for both LCQ and NLHQ), a Bonferroni correction was applied and the threshold for significance was considered to be p=0.025. To assess the relationship between BMI or cough duration and pre-post changes in LCQ and NLHQ, Spearman correlation analyses were performed.

Results

Participants

The study sample comprised 19 adults with unexplained chronic cough (Table1). Their mean age was 66.8 (SD ±7.7) years. Eighteen individuals (95%) identified as White, 1 (5%) identified as Asian/Asian American, and none identified as being of Hispanic ethnicity or Spanish origin. Mean BMI of the participants was 27.1 (SD ±5.6). The mean chronic cough duration was 129.6 months (SD ±110.4). Cough severity was self-rated using a scale of 0 (no cough) to 100 (worst possible cough) with a mean of 63.1 (SD ±17.2). When asked to rate the severity of their cough problem, 8 (42%) of participants reported their cough to be a moderate problem, 7 (37%) a big problem, and 4 (21%) a very big problem.

Table 1:

Demographic and clinical descriptors of the participants.

ID	Age (years)	Sex	Race (not Hispanic/ Latino)	BMI	Chronic cough duration (months)	How much of a problem is your cough?	Baseline LCQ	Cough severity VAS
1	65	M	Asian	25	60	Moderate	10.44	40
2	62	F	White	32	48	Moderate	10.91	50
3	73	M	White	33	72	Moderate	11.71	61
4	64	F	White	29	36	Moderate	7.23	70
5	76	F	White	24	180	Very big	8.54	78
6	74	M	White	36	9	Moderate	14.04	70
7	69	M	White	37	240	Moderate	11.77	75
8	63	F	White	24	156	Very big	11.00	62
9	71	F	White	28	336	Moderate	9.63	47
10	61	F	White	23	84	Big	12.61	75
11	53	F	White	39	12	Big	10.21	73
12	56	M	White	22	360	Big	12.34	55
13	52	F	White	23	216	Very big	9.69	80
14	69	F	White	22	15	Moderate	11.45	52
15	72	F	White	21	216	Very big	6.14	82
16	64	M	White	23	180	Big	13.98	26
17	76	M	White	28	2	Big	9.86	90
18	74	F	White	23	60	Big	11.09	75
19	76	M	White	24	180	Big	9.70	45
Mean (SD)	66.8 (7.7)	-	-	27.1 (5.6)	129.6 (110.4)	-	10.65 (2.01)	63.5 (16.8)
Median	69	-	-	24	84	-	10.91	70

BMI = body mass index. LCQ = Leicester cough questionnaire. VAS - visual analogue scale.

Feasibility and Acceptability

Overall, laryngeal VTS use was feasible and acceptable to the study participants. No adverse events were reported. All participants completed the baseline and final assessments. Almost all (93%) of planned VTS sessions were logged. Regarding usability, 94% of participants felt that laryngeal VTS was comfortable to wear, 89% felt it was easy to operate, and 79% said they would recommend it to a friend with a similar cough problem.

Leicester Cough Questionnaire Scores

The mean baseline LCQ score was 10.65 (SD ±2.01) and the mean LCQ total score after VTS application was 11.94 (SD ±2.88). This represented a mean improvement of 1.29 (SD ±2.38, 95%CI [0.14, 2.44], p = 0.015) on the LCQ (Figure 1), which is comparable to the established MID of 1.3.²³ When examined individually, 10 (53%) participants observed a change exceeding MID of 1.3, 5 (26%) observed a modest increase in LCQ that did not exceed the MID, and 5 (26%) observed a modest decrease in LCQ score.

Figure 1.

Individual LCQ scores at baseline (Pre) and after the application of VTS (Post). The data depicted in the boxplot represent the distribution of the difference scores between the two time points. Upper and lower bounds of the box are 25%ile and 75%ile; center line is the median, and upper and lower whiskers represent the minimum and maximum (excluding outlier, ±1.5*IQR, indicated by circle). The diamond represents the mean change, with whiskers within the box representing the 95% confidence interval.

Newcastle Laryngeal Hypersensitivity Questionnaire Scores

The mean baseline NLHQ score was 14.6 (SD ±2.16) and the mean NLHQ score after VTS application was 16.11 (SD ±2.30). This constituted a statistically significant mean improvement of 1.52 (SD ±1.51, 95% CI [0.79, 2.24], p = 0.0002) in NHLQ (Figure 2), which is less than the pre-specified MID of 1.75.¹⁹ At an individual level, 7 (37%) participants observed an increase in NLHQ that exceeded the MID of 1.75, 9 (47%) observed an increase in NLHQ that did not reach the MID, and 3 (16%) observed a modest decrease in NLHQ.

Figure 2.

NLHQ scores at baseline (Pre) and final (Post), and a boxplot of the difference between the two time points. Upper and lower bounds of the box are 25%ile and 75%ile; center line is the median, and upper and lower whiskers represent the minimum and maximum (excluding outliers, ±1.5*IQR). The diamond represents the mean change, with whiskers within the box representing the 95% confidence interval.

Correlation with Demographic Characteristics

There was no correlation between change in LCQ and BMI or cough duration. Similarly, change in NLHQ did not correlate with BMI or cough duration. Additionally, the baseline LCQ score and mean change in LCQ were not correlated.

Discussion

This study demonstrated that the application of laryngeal VTS use was feasible and acceptable for our sample of participants with unexplained chronic cough. Given the laryngeal hypersensitivity often reported by individuals with chronic cough, this was not a foregone conclusion. However, vibration has been helpful in other neuropathic disorders such as chronic pain²⁵ and pruritus,²⁶ which may represent an informative parallel.

The changes in LCQ and NLHQ observed in this study were positive yet relatively modest, although they fell within range of some studies examining the effect of other treatments for chronic cough.^27–29 There was heterogeneity across individuals, suggesting potentially differential responsiveness. Analyses suggested that these differences were not accounted for by BMI (which could potentially affect the amount of vibrotactile stimulation reaching the endolarynx) or cough duration or severity. Interestingly, responsiveness on the LCQ and NLHQ also did not necessarily track together, with some individuals indicating improvement on one scale but not the other. This may be because the measures, while related, assess different aspects of the experience of living with chronic cough, in which the LCQ reflects cough-related quality of life whereas the NLHQ reflects laryngeal and throat sensations. It is possible, for example, that laryngeal VTS use might increase attention to laryngeal and throat sensations, leading to a persistently elevated NLHQ even if cough as reflected by LCQ score improved. Conversely, it is possible that a person with persistent cough but reduced throat irritation might have an unchanged LCQ score while having a lower NLHQ score. It remains to be seen whether laryngeal VTS might have a greater impact on particular aspects or endotypes of chronic cough.³⁰

As it is a first step in this line of inquiry, this study has important limitations, including its single arm non-blinded design, small sample size, and early nature of the study protocol. We cannot exclude that part of the reported improvements constitute a placebo effect, which has been observed in other studies of unexplained chronic cough.³¹ It is imperative to replicate these findings in a larger, more diverse sample, which would also potentially allow subgroup analyses. In addition, some participants expressed an interest in either longer use sessions or more weeks of use, suggesting that the initial dosing, though acceptable, needs further optimization. Finally, while patient-reported outcomes such as LCQ and NLHQ are critically important when examining disorders with a major quality of life impact, they are imperfectly correlated with objective measures such as cough counts,³² and future studies will need to incorporate a multidimensional assessment of potential VTS effects on cough symptoms.

Despite these limitations, these findings represent an informative first step of inquiry regarding the potential use of laryngeal VTS as a symptomatic treatment for unexplained chronic cough. Laryngeal VTS is appealing as it is non-invasive, repeatable, portable and is not associated with systemic side effects. Future studies will need to incorporate dose refinement, comparators, larger sample sizes, and objective cough counts to determine whether this approach could lead to a potential additional treatment modality for unexplained chronic cough.

Conclusion

Laryngeal VTS was feasible and acceptable for use by patients with chronic cough and was associated with a meaningful improvement in cough-related quality of life measures. This study serves as a foundation for future work investigating the potential use of laryngeal VTS for unexplained chronic cough.