The Impact of Medical Comorbidities on Cough Improvement Following Superior Laryngeal Block

Introduction

Cough consistently remains a top reason for which patients seek medical care in the United States.^1,2 Chronic cough, which is defined as cough lasting greater than 8 weeks^{3 -5} can significantly impact patients’ quality of life.^6,7 Common causes of chronic cough include gastroesophageal reflux disease (GERD), allergies, asthma, and infection. When chronic cough continues to persist, despite adequate treatment, the cough can be considered to be triggered by a hyper-reflexive neuropathy of the superior laryngeal nerve (SLN),^1,8 the internal branch of which (iSLN) provides sensory innervation to the laryngeal mucosa superior to the vocal folds. ⁹ This hyper-reflexive and hyper-sensitive state commonly occurs after viral illness. ⁸ Treatments for neuropathic pain, such as gabapentin, pregabalin, and amitriptyline, are common medical treatments for refractory cough, as there are pathophysiological similarities between chronic cough and chronic pain.^10,11 Another nonpharmacologic treatment option for chronic refractory cough is cough modulating therapy with speech language therapy. While this option does not have the side effects of medication therapy, studies cite short-lived results and have inconclusive findings with regards to its efficacy. ¹²

In addition to medical treatments and cough modulating therapy,^1,13 iSLN nerve blockade has been successful in improving presumed laryngeal hypersensitivity cough symptomatology.^8,14 In 2018, Simpson et al ¹⁴ demonstrated significant improvement in cough in a cohort of 23 patients treated with iSLN blockade using a combination of local anesthetic and corticosteroid. Since then, similar results have been reported by several groups,^{8,15 -17} and iSLN blockade has been shown to be effective in reducing Cough Severity Index (CSI) scores as long as 10 months post-procedure. ¹⁸ While these studies have largely characterized iSLN blockade as safe and efficacious, there is currently a lack of consensus on whether patients might differentially benefit from iSLN block. Duffy et al, ¹⁵ for example, found that only patients with vocal fold abnormalities had a statistically significant improvement in short-term CSI score after iSLN block, while Talbot et al ¹⁶ found no positive predictors of response to iSLN blockade in a cohort of 54 patients. Thus, more work remains to thoroughly characterize which patients will benefit most from iSLN blockade. We hypothesize that patients who undergo iSLN blockade have differential CSI improvements based on their underlying laryngeal or respiratory comorbidities.

Methods

The study population included adult patients aged 18 years or older evaluated at our institution’s laryngology clinics between 2019 and 2022. All patients carried a diagnosis of chronic refractory cough due to presumed laryngeal hypersensitivity established by a fellowship-trained laryngologist and underwent iSLN block. This study was deemed exempt by our University’s Institutional Review Board. Electronic medical records (EMR) were reviewed to collect data on patient demographics, medical comorbidities, pre- and post-operative CSI surveys, videostrobolaryngoscopy data, adverse events as well as current medications taken by patients during the time of their laryngology evaluation and procedure. Videostrobolaryngoscopy findings used to assess vocal fold symmetry and mobility were evaluated by the laryngologist during the clinic visit and the subsequent notes were reviewed in the EMR for analysis in this study.

Patients with multiple preoperative CSI scores had an average of all values used for the preoperative value in percent-change calculations. For patient undergoing more than 1 iSLN block, CSI scores at the conclusion of treatment were used for analysis. The iSLN block protocols at our institution utilizes either 0.5 cc of 2% lidocaine + 0.5 cc of dexamethasone sodium phosphate (dexamethasone-10), or 1 cc of dexamethasone sodium phosphate + 1 cc of 0.5% bupivacaine. Triamcinolone is avoided as it is a particulate steroid and can embolize. Sidedness of the injection depends on whether there is a trigger point; otherwise, either side is injected at random. Patients are asked to return in 2 to 4 weeks. Additional injections are given based on the patient-reported response at the subsequent follow-up visit.

These scores were collected at subsequent follow-up visit, which occurred on average 4 weeks after the final block. Statistical analysis was conducted in SPSS v. 28 (Armonk, NY, USA). Two-tailed independent sample T tests were used to compare means and standard deviations between patients who had various comorbid conditions or evidence of paresis or vocal fold motion asymmetry on videostrobolaryngoscopy against those who did not. P-values less than or equal to .05 were considered statistically significant.

Results

Demographic and Comorbidity Data

Our cohort included 44 patients (22.7% male) with an average age of 61 ± 11.0 years. The average percent improvement seen in CSI scores post-treatment was 30.0 ± 34.7. The median number of iSLN blocks that the patients received was 2 with the average time between blocks being 1.5 months. Only 1 patient had an adverse event, which was a brief vasovagal episode from which the patient recovered quickly with no further sequelae. About 31.8% of patients had a former smoking history, 4.5% had sinonasal disease, 54.5% had pulmonary disease, and 77.3% had a diagnosis of GERD. Common pulmonary comorbidities included asthma, bronchitis, or chronic obstructive pulmonary disease (COPD). About 91.2% of the patients with GERD were on proton pump inhibitors (PPIs) for their disease, 64.4% of the patients with pulmonary or upper airway disease were on antihistamines, steroids or anti-inflammatory medication, and 11.1% of patients were on neuromodulating medications. The aforementioned comorbid conditions are not mutually exclusive for the patients in our study. About 27.3% of the cohort had positive findings on stroboscopy defined as paresis or vocal fold motion asymmetry (Table 1). At the time of the procedures, these patients had not received any other treatment for their asymmetric findings.

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Table 1.

Subject Demographics.

Factor	Variable	Total (n = 44)
Age (years)	(Mean ± SD)	61 ± 11.0
BMI	(Mean ± SD)	29.2 ± 5.8
CSI (% improvement)	(Mean ± SD)	30.0 ± 34.7
iSLN blocks	(Median)	2
Time between blocks (months)	(Mean ± SD)	1.47 ± 1.19
Sex	% (n)
Male		22.7 (10)
Female		77.3 (34)
Smoking	% (n)
Never		68.2 (30)
Former		31.8 (14)
Past medical history	% (n)
Sinonasal		4.5 (2)
Pulmonary disease		54.5 (24)
GERD		77.3 (34)
Adverse events	% (n)	2.25 (1)
Positive stroboscopy findings a	% (n)	27.3 (12)

Abbreviation: GERD, gastroesophageal reflux disease.

a

Defined as vocal fold paresis or asymmetry.

Comparisons in CSI Score Improvements

When comparing the average percent change in CSI scores after iSLN block treatment in patients in with and without history of GERD, or former versus never smokers, the findings were not significant (P = .36 and 0.85, respectively; Table 2). When comparing CSI outcomes in patients with and without pulmonary disease history, patients without pulmonary comorbidities had a greater percent improvement post-treatment than those with a history of disease (47.7 ± 38.1 vs 9.85 ± 15.0, P = .028). The average number of blocks for those with a history of pulmonary disease compared to those without is 2.25 versus 1.70 (P = .079). When comparing CSI outcomes in patients with and without positive stroboscopy findings, there were no significant differences (P = .195).

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Table 2.

Comorbidities Affecting Percent Change in Cough Severity Index (CSI) After Treatment.

% Change in CSI after treatment	Mean ± 95% CI (%)	P value
GERD history		.36
Yes	22.5 ± 26.4
No	45.0 ± 47.1
Pulmonary history		.028
Yes	9.85 ± 15.0
No	47.7 ± 38.1
Smoking history		.85
Former	32.7 ± 27.8
Never	29.0 ± 38.0
Stroboscopy findings (paresis or asymmetry)		.195
Yes	41.3 ± 18.8
No	27.2 ± 37.7

Abbreviation: GERD, gastroesophageal reflux disease.

Discussion

In this work, we sought to characterize whether patients differentially benefit from iSLN blockade depending on their medical comorbidities. To our knowledge, this is the first study to assess changes in cough severity in a numerical manner and show a significant difference in CSI outcomes post-treatment when comparing those with and without a medical comorbidity. Specifically, we found that patients with underlying pulmonary diseases (asthma, chronic bronchitis, or COPD) had a significantly attenuated response to iSLN blockade compared to patients without the same comorbidities.

One of the reasons that the improvement of patients can be attributed partially to the iSLN blockade is because a large percentage of patients (>64%) were already on other medications such as neuromodulators, steroids, antihistamines, etc. to presumably help with their symptoms. However, despite being on those medications, the measurable relief, seen in CSI improvement, came after the nerve block procedure.

In patients with post-infectious chronic refractory cough, the most common initial trigger is an upper respiratory infection. ¹⁹ Hypersensitivity of the iSLN fits this symptom picture, suggesting that iSLN blockade could provide significant relief to patients with upper respiratory sensitivity. However, in patients with chronic cough and underlying lower respiratory pathologies such as asthma, chronic bronchitis, and COPD, laryngeal hypersensitivity may be only 1 of multiple stimuli acting on the cough reflex. The afferent arm of the cough reflex in the lower respiratory tract is innervated by different sensory branches of the vagus nerve.^20,21 As such, blockade of the iSLN may not adequately address cough that is exacerbated by underlying pulmonary conditions such as bronchial hyperresponsiveness due to cough-variant asthma ²² or mucous metaplasia as is seen in chronic bronchitis. ²³ While iSLN block may provide some relief to patients by decreasing laryngeal hypersensitivity, this procedure does not target all hypersensitive cough-related afferents in patients with underlying pulmonary disease. In support of this idea, more iSLN blocks were needed, on average, for patients with underlying pulmonary disease compared to those without lung disease. Though this difference did not reach statistical significance, it is likely due to the low power nature of this study.

Interestingly, while patients with underlying pulmonary disease differentially benefitted from iSLN block for their chronic cough, there was no difference in CSI improvement between former- and never-smokers. This is perhaps due to the fact that persistent smoking has been reported to blunt—rather than hyperactivate—the cough reflex, ²⁴ and that this blunting effect decreases as quickly as 2 weeks after smoking cessation. ²⁵ As we compared only former and never smokers, our results are consistent with the idea that, in the absence of underlying respiratory pathology, smoking leads to a reversable blunting of the cough reflex and does not have a physiologically significant impact on the effectiveness of iSLN blockade.

With regards to patients with GERD, our study showed no difference in cough outcomes after iSLN treatment. An important factor to consider is that over 90% of the patients in our cohort were on PPI treatment. Due to its protective mechanism, PPI use may have mitigated the negative effects of the disease making the physiology of those with and without GERD similar enough to not see an effect of the procedure. Another interesting point is that when comparing patients with GERD versus patients with pulmonary disease, we saw that patients who had GERD saw a greater degree of improvement in their CSI score after the iSLN block than those with pulmonary diseases (22.5% vs 9.85%). Compared to pulmonary diseases, GERD cough physiology happens when gastric acid and other stomach contents move from the stomach to the trachea/larynx with a lower esophageal sphincter that has decreased tone. Therefore, it may follow that GERD chronic cough is a more direct irritant of the iSLN than asthma/pulmonary disease, which have a hyperexcitable cough reflex as a whole.^19,26 Another possible mechanism for cough reflex related to GERD is the stimulation of afferent C-fiber on the esophageal mucosa. It is hypothesized that the afferent nerve fibers mediating cough sensitization in the esophagus are derived from the vagal jugular C-fibers. ²⁷ Thus, it is possible that the iSLN block could play a role in mitigating the cough reflex via reducing stimulation of these receptors as well.

When looking at patient CSI outcomes on the basis of vocal fold paresis or asymmetry, though we did not see a statistically significant difference, we did see a trend supporting the idea of greater improvement in this subgroup. One explanation is that patients with vocal fold paresis or asymmetry possibly subsequently develop hyperexcitability of nerves innervating nearby structures, including of the SLN. As a result, refractory cough from laryngeal hypersensitivity could be alleviated by broad lidocaine-mediated blockade of SLN firing. However, it is important to note that vibratory asymmetry in the setting of presumed laryngeal hypersensitivity can be indicative of involvement of the entire SLN including both the internal and external branches. This extensiveness could be an explanation as to why our trend was not strong enough to reach significance as the block primarily targets only the internal branch.

Though this study is the first to quantify improvement in chronic cough after comparing patients with and without specific comorbidities, it is not without limitations. The sample size of this study is small, and therefore we were not powered enough to isolate each of the comorbidities being studied through multivariate analysis. Further research is needed to validate our findings and confirms the trends seen. Additionally, while post-procedure CSI values were present for patients after the final nerve block, CSI values were not collected between multiple blocks for patients who had more than 1. Thus, we were unable to evaluate how repeated procedures impacted the progression of disease improvement. Future prospective studies should consider characterizing this aspect of chronic cough management to help guide patients on the number of blocks necessary to achieve maximal percentage improvement.

Another limitation of our study is that while we are investigating the impact of specific comorbidities on procedure outcomes, we did not control for other concurrent health issues that could differentially impact a patient’s degree of improvement due to statistical test limitations. Thus, while our findings suggest that patients with a certain comorbid profile may benefit more than others, individualized counseling is still necessary since the presence of several health concerns could impact the outcomes. Prospective studies can also aim to standardize pre-treatment medication therapy trials for patients to more accurately isolate the benefits seen from this procedure and assess its effectiveness in comparison to medication management. Additionally, it is important to note that the original application of the iSLN blockade utilized a particulate steroid, different from the steroids used in this study, and thus that deviation from the methodology may contribute to our results.

Our study also did not assess long-term effects of the iSLN block. Future studies may benefit from assessing the longevity of this procedure and the expected long-term outcomes for patients.

Conclusion

In conclusion, iSLN blocks is an effective treatment that improves the CSI score in patients who do not have comorbid pulmonary disease compared to those who do and may also be more beneficial for those who have vocal fold paresis or asymmetry. These aspects of a patient’s medical history and their differential effects on treatment outcomes should be considered when counseling patients on the efficacy of treatment options for refractory cough from laryngeal hypersensitivity.