HYPERVIGILANCE AND ANXIETY ARE ELEVATED AMONG PATIENTS WITH LARYNGEAL SYMPTOMS WITH AND WITHOUT LARYNGOPHARYNGEAL REFLUX

Research Letter

A majority of patients experiencing laryngeal symptoms are labeled as having laryngopharyngeal reflux (LPR).¹ LPR has classically been defined as an extra-esophageal manifestation of gastroesophageal reflux disease (GERD) in which gastric refluxate leads to irritation of and increased nociception at the upper aerodigestive tract.² Diagnosis of LPR poses a significant challenge to clinicians and patients. For instance findings on laryngoscopy graded according to the validated reflux finding score (RFS) are non-specific for LPR since multifactorial etiologies including postnasal drip or allergies can result in an elevated RFS.² Similarly, patient reported symptoms as measured by several validated instruments (e.g., Reflux Symptom Index) have poor prognostic performance in predicting laryngeal symptom response.³ Since not all laryngeal symptoms are driven by acidic refluxate, hence often not responsive to traditional anti-reflux therapies, current guidelines and best practice updates recommend ambulatory reflux monitoring off acid suppression in patients with isolated LPR symptoms prior to a trial of proton pump inhibitor (PPI) therapy.² Further, a recent study demonstrated that patients with laryngeal symptoms present with distinct phenotypes (e.g., LPR/GERD, LPR/hypersensitivity, no LPR/no GERD), among which cognitive-affective processes may drive symptom burden to varying degrees across phenotypes.¹

This notion that cognitive-affective processes impact symptom severity and quality of life in the realm of typical GERD is increasingly accepted, and consequently gut-directed behavioral therapies are recommended across the spectrum of GERD.⁴ Further, the validated esophageal hypervigilance and anxiety scale (EHAS) patient report instrument assesses levels of symptom associated anxiety and hypervigilance.⁵ One such questionnaire, the Newcastle Laryngeal Hypersensitivity Questionnaire, was validated for LPR; however, unlike the EHAS, it focuses on symptoms rather than the impact of cognitive-affective processes on symptom perception.⁶ Unfortunately, the current paradigm for LPR largely ignores the interplay of psychological stressors on symptom burden.⁷ This dearth of research in the role of psychological stressors and behavioral therapy is a tremendous missed opportunity to help patients with chronic laryngeal complaints. In attempt to address this knowledge gap, we aimed to measure hypervigilance and anxiety in patients with laryngeal symptoms and compare hypervigilance and anxiety levels between symptomatic patients with and without LPR.

This single center observational study enrolled patients over two years (9/2019–9/2021). Patients were included if they were adults with laryngeal symptoms (cough, dysphonia, throat clearing, sore throat, mucous in throat, globus) that underwent ambulatory reflux monitoring off acid suppression and completed the EHAS. Patients were defined as having true LPR if acid exposure time (AET) on reflux monitoring was ≥ 6% (LPR+) and no LPR if AET < 6% (LPR−). The study was approved by the IRB. See supplemental materials for methods.

A total of 77 patients are included in the analysis: mean age 49.8 years (SD 15.3) and 60 (78%) female. Twenty-two (29%) met criteria for LPR+ (mean AET 13.1% (11.7)) and 55 (71%) met criteria for LPR− (mean AET 1.7 (1.6)). (Table 1). Mean BMI was significantly higher in the LPR+ vs LPR− group (28.0 (6.4) vs 24.7 (4.1), p=0.01). There were no significant differences between age, sex, GerdQ or RSI scores between groups.

Table 1:

Patient Characteristics

	LPR− (AET < 6%), n=55	LPR+ (AET ≥ 6%), n=22	P-Value
Age (years)	49.8 (SD 15.8)	49.8 (SD 14.3)	0.99
Female sex	46 (84%)	14 (64%)	0.06
Body mass index (kg/m2)	24.7 (SD 4.1)	28.0 (SD 6.4)	0.01
Esophageal acid exposure time (%)	1.7 (SD 1.6)	13.1 (SD 11.7)	<0.001
GerdQ score	7.2 (SD 3.2), n=54	8.6 (SD 3.5), n=21	0.09
Reflux symptom index score	19.1 (SD 9.2)	20.9 (SD 8.2)	0.43
EHAS Total	33.2 (SD 14.9)	35.0 (SD 12.8)	0.62
EHAS Q1-9 (anxiety domain)	20.5 (SD 10.1)	20.5 (SD 9.5)	0.99
EHAS Q10-15 (hypervigilance domain)	12.7 (SD 5.9)	14.5 (SD 5.6)	0.22
Elevated EHAS score (> 21)	45 (82%)	19 (86%)	0.63

Depicted as mean (SD) for continuous variables or n (%) for categorical variables. EHAS, esophageal hypervigilance and anxiety scale; LPR, laryngopharyngeal reflux

A similarly high proportion of patients in both groups reported elevated EHAS scores (45 (82%) LPR− and 19 (86%) LPR+; p=0.63). Mean total EHAS scores were similar in the LPR− and LPR+ groups (33.2 (SD 14.9) vs 35.0 (SD 12.8); p=0.62). EHAS-anxiety and EHAS-hypervigilance sub-scores were not significantly different between LPR− or LPR+ groups (Supplemental Figure 1). There was no difference in EHAS score between the LPR− and LPR+ groups (OR 1.01 (95% CI 0.97, 1.05); p=0.67), which was maintained in a multivariable regression model adjusting for sex, BMI, and GerdQ score (OR 1.01 (95% CI 0.97, 1.05); p=0.67).

Similar patterns were noted in the sensitivity analysis where an AET cut-off of 4% was utilized to categorize LPR+/LPR− groups (Supplemental Table 1).

In summary, individuals with laryngeal symptoms represent a heterogenous group with varying symptoms and pathologies, and often pose a challenge for clinicians. In this study of 77 patients with laryngeal symptoms, less than one-third met criteria for true LPR, highlighting that a significant portion of patients with laryngeal symptoms presenting for evaluation do not have concomitant GERD, and are unlikely to benefit from reflux-targeted therapies. Further, both groups with and without true LPR reported elevated levels of hypervigilance and anxiety, suggesting that cognitive affective processes are inter-related with laryngeal symptom burden regardless of reflux physiology, and may represent an important therapeutic target.

The concepts of cognitive affective processes driving or contributing to esophageal symptom burden, rather than solely pathologic reflux events, is well accepted in GERD.⁸ These functional esophageal disorders are noteworthy because they are poorly understood and can have implications in patient quality of life and healthcare utilization.⁷ As such a pillar of treatment in GERD aims to target these processes with stress reduction, pharmacologic neuromodulation and gut-directed behavioral therapy.⁹ While the concept of a functional laryngeal disorder has been proposed, there is a dearth of data to support and guide management.¹⁰ Some researchers propose laryngeal hyperresponsiveness could be due to an exaggerated response to stimuli, in that certain patients are more sensitive to certain laryngeal sensations.¹⁰ Our study is the first to identify elevated levels of hypervigilance in patients with and without true LPR, suggesting a physio-psychological interplay of factors that modulate symptom burden in LPR and highlighting the potential of integrative treatment approaches beyond reflux targeted therapy. Future studies evaluating response to behavioral and speech treatments directed at cognitive affective processes are needed. Further, a validated patient report instrument to measure laryngeal symptom specific hypervigilance and anxiety will be of value rather than reliance on the EHAS.

Strengths of the study include that all patients were well-characterized on the basis of their reflux monitoring data, rather than reliance on presence of symptoms alone. Limitations include the observational nature of the study without outcomes data.

In conclusion, this study highlights that the majority of patients presenting with laryngeal symptoms do not have pathologic GERD and suggests that therapies targeting cognitive-affective processes are an essential component of treatment, regardless of their physiologic acid exposure burdens.

Abbreviations:

LPR

Laryngopharyngeal Reflux

EHAS

Esophageal hypervigilance and anxiety scale

AET

Acid exposure time

GERD

Gastroesophageal reflux disease

GerdQ

Gastroesophageal Reflux Questionnaire

RSI

Reflux Symptom Index

BMI

Body mass index

PPI

Proton pump inhibitor