Abstract
Background:
Patients with chronic laryngopharyngeal symptoms, with or without pathologic reflux, frequently have poor response to standard therapies, which may be a result of overlapping cognitive-affective processes. Therefore, the aims of this study included measuring psychosocial distress and laryngeal-specific cognitive distress in patients with chronic laryngopharyngeal symptoms (LPS) as well as comparing these among laryngeal symptomatic patients with and without conclusive gastroesophageal reflux disease (GERD).
Methods:
This prospective, single-center study enrolled adults with chronic LPS from 9/22 to 6/23. Patients completed eight questionnaires on quality of life, symptom burden, and psychosocial distress. The laryngeal cognitive affective tool (LCAT) assessed laryngeal-specific hypervigilance and anxiety; LCAT scores ≥33 were elevated. All patients underwent objective testing with endoscopy and/or ambulatory reflux monitoring and were categorized as proven GERD (GER+) or no proven GERD (GER−).
Key Results:
One hundred twenty-nine patients were included: 66% female, mean age 54.1 (17.5) years, mean BMI 27.6 (6.8) kg/m2, 66% Caucasian, 57% with an elevated LCAT, and 53% GER+. Moderate-to-severe anxiety was found in 39% and moderate-to-severe depression in 19%. An elevated LCAT alone or with an elevated anxiety/depression score was found in 58%. Patient-reported outcomes scores, including LCAT scores (32.9 (13.8) GER− vs. 33.1 (12.6) GER+, p = 0.91), were similar between patients with and without GER+.
Conclusions and Inferences:
Patients with chronic LPS experience heightened levels of hypervigilance, symptom-specific anxiety, and psychosocial distress, regardless of the presence of pathologic GER.
Keywords: anxiety, depression, laryngopharyngeal reflux, quality of life
Graphical Abstract
Patients with chronic laryngopharyngeal symptoms (LPS) experience elevated hypervigilance, symptom-specific anxiety, and psychosocial distress regardless of the presence of pathologic reflux. These findings suggest that therapies targeting cognitive-affective processes and hyperresponsive behaviors are essential to improve quality of life in these patients.
1 |. INTRODUCTION
Laryngopharyngeal symptoms (LPS) are highly prevalent, affecting 5%–30% of the general population.1–5 Based on symptoms alone, many patients are inappropriately diagnosed with gastroesophageal reflux disease (GERD) and consequently treated with reflux targeted therapies.1,6 Unfortunately, these patients often do not experience symptom improvement, which can lead to multiple diagnostic tests and provider referrals, which is costly from an economic standpoint and negatively impacts patient well-being.7,8 Identifying and managing comorbid psychosocial impairment is instrumental in these patients.
Though still in its infancy, a growing body of evidence suggests that patients with chronic LPS experience impaired quality of life (QOL) and heightened hypervigilance and symptom-specific anxiety, regardless of the presence of pathologic GERD.8–11 The literature is not robust and the few available studies have utilized the esophageal hypervigilance and anxiety scale (EHAS), which is meant to assess esophageal, rather than LPS-specific hypervigilance and anxiety. The recently validated Laryngeal Cognitive Affective Tool (LCAT) can be used to evaluate symptom-specific hypervigilance and anxiety in patients with chronic LPS.12 Therefore, the aims of this study included measuring psychosocial distress and laryngeal-specific cognitive distress in patients with chronic LPS as well as comparing these among laryngeal symptomatic patients with and without conclusive GERD.
2 |. MATERIALS AND METHODS
2.1 |. Study design and data collection
This prospective, single-center study enrolled patients over 9 months (9/2022–6/2023). English speaking adults (18–99 years old) experiencing chronic LPS (i.e., mucus in throat, throat clearing, cough, dysphonia, globus sensation, and sore throat) for 6 months or longer undergoing objective testing for laryngopharyngeal reflux disease (LPRD) were recruited from outpatient Gastroenterology clinic visits and procedures. Participants were excluded if they could not consent, self-complete patient-reported questionnaires without being read to them, use a computer or smart device to complete the questionnaires, if they were imprisoned, had prior foregut surgery or an inconclusive GERD status (e.g., borderline endoscopic findings such as Los Angeles A esophagitis or short segment Barrett’s esophagus without confirmatory reflux monitoring data). A survey link through UCSD Research Electronic Data Capture (REDCap)13,14 was provided to participants and after consenting, participants completed a series of online questionnaires. Participants received compensation for their participation.
Electronic medical records of patients were retrospectively reviewed. Data collected included demographic information as well as findings from esophagogastroduodenoscopy (EGD), including Los Angeles Classification, length of Barrett’s esophagus, and ambulatory reflux monitoring. Data were collected in Research Electronic Data Capture. This study was funded by NIH DK135513 and the protocol was approved by the Institutional Review Board (IRB).
2.2 |. Questionnaires
Patients completed a series of questionnaires: LCAT,12 Gastroesophageal Reflux Disease Questionnaire (GerdQ),15 Illness Cognition Questionnaire (ICQ),16 Northwestern Esophageal Quality of Life Questionnaire (NEQOL),17 Patient-Reported Outcomes Measurement Information System (PROMIS) for Anxiety and Depression,18 Voice Handicap Index (VHI),19 and Reflux Symptom Index (RSI).20 Questionnaire domains of focus, scoring, and outcome measures are summarized in Table 1. The LCAT is a newly validated questionnaire that assesses symptom-specific hypervigilance and anxiety in patients with chronic LPS. In this study, the previously published median split was used and identified a score of ≥33 as elevated.12
TABLE 1.
Patient reported outcomes questionnaires.
| Questionnaire | Domains of focus | Scoring | Outcome measures |
|---|---|---|---|
|
| |||
| LCAT | Hypervigilance and symptom-specific anxiety | 0–60 | ≥33 abnormal |
| GERDQ | GERD symptoms | 0–18 | ≥8 abnormal |
| ICQ | Helplessness, acceptance, perceived benefits | 6–24 each domain | – |
| NEQOL | Esophageal symptoms on quality of life | 0–56 | – |
| RSI | Laryngopharyngeal symptoms | 0–45 | >13 abnormal |
| VHI | Voice symptoms on quality of life | 0–120 | 0–30 mild 31–60 moderate 61–120 severe |
| PROMIS anxiety | Anxiety | Raw scores are converted into | 7-scores: |
| PROMIS depression | Depression | 7-scores | <55 none or slight 55.0–59.9 mild 60.0–69.9 moderate ≥70 severe |
2.3 |. GERD evaluation
Ambulatory reflux monitoring systems included two configurations: prolonged wireless single pH capsule (Bravo; [Medtronic, Minneapolis, MN]) or 24-h multichannel intraluminal impedance pH monitoring [Medtronic].
Proven GERD (GER+) was defined as: LA Grades B/C/D esophagitis and/or long segment Barrett’s esophagus (≥3 cm) on endoscopy, esophageal acid exposure time (AET) ≥ 6% and/or ≥ 80 reflux events/24 h on ambulatory reflux monitoring off PPI, or AET ≥2% and/or ≥ 40 reflux events on impedance-pH on PPI.21 Unproven GERD (GER−) was defined as a negative ambulatory reflux monitoring study off PPI (AET <6% and < 80 reflux events/24 h). Patients with LA Grade A esophagitis, short-segment Barrett’s esophagus, or a negative 24 h pH-impedance study on PPI, who did not also have reflux testing off PPI, were excluded due to an inability to conclusively rule out GERD.
2.4 |. Statistical analyses
Missing data were not imputed. Demographic data were analyzed as mean and standard deviations or percentages.
Primary analyses evaluated the prevalence of anxiety, depression, and laryngeal-specific hypervigilance and symptom-specific anxiety in all participants included in this study, regardless of the presence or absence of pathologic GERD.
Secondary analyses compared patient-reported outcomes (PRO) scores between symptomatic patients with (GER+) or without (GER−) GERD. Two-sample t-tests were used for continuous variables and Pearson’s chi-square test or Fisher’s exact test, for small sample sizes, were used for categorical variables. Analyses were conducted via R v4.2.0 (Vienna, Austria).
3 |. RESULTS
3.1 |. Baseline characteristics
From 204 symptomatic participants, 75 were excluded, due to inconclusive GERD status or prior foregut surgery. A total of 129 patients were included: 84 (66%) female, mean age 54.1 (17.5) years, mean BMI 27.6 (6.8) kg/m2, 84 (66%) Caucasian. Overall, 69 (53%) patients met criteria for GER+; 4 (6%) with Los Angeles Grade B Esophagitis, 1 (1%) with Los Angeles Grade C Esophagitis, 1 (1%) with Los Angeles Grade D Esophagitis, 2 (3%) with long-segment Barrett’s esophagus, 46 (67%) with GER+ on prolonged-wireless reflux monitoring off PPI, 11 (16%) with GER+ on 24-h multichannel intraluminal impedance pH monitoring off PPI, and 10 with GER+ on 24-h multichannel intraluminal impedance pH monitoring on PPI. Notably, some individuals had multiple studies. Overall, 73 (57%) patients reported an elevated LCAT score of ≥33.
3.2 |. Prevalence of anxiety, depression and elevated laryngeal hypervigilance and anxiety
In total, 39% (49/127) reported moderate-to-severe anxiety and 19% (24/126) reported moderate-to-severe depression. Normal LCAT scores with normal/mild anxiety or depression were found in 33% (41/126). Elevated LCAT scores alone or with moderate-to-severe anxiety/depression were found in 73/126 (58%). Moderate-to-severe anxiety/depression with normal LCAT scores were found in 12/126 (10%) (Figure 1).
FIGURE 1.
In patients with chronic laryngopharyngeal symptoms, 33% experienced normal or mild psychosocial distress, 30% experienced an elevated laryngeal cognitive affective tool (LCAT) with moderate–severe anxiety/depression, 28% experienced an elevated LCAT with normal or mild psychosocial distress, and 10% experienced moderate–severe depression and/or anxiety without an elevated LCAT.
3.3 |. Secondary analyses comparing patients with and without proven GERD
Comparing GER+ to GER− patients, 23/67 (34%) of GER+ and 26/60 (43%) of GER− patients (p = 0.30) reported moderate-to-severe anxiety and 11/66 (17%) GER+ and 13/60 (22%) GER− (p = 0.48) (Table 2) reported moderate-to-severe depression. Total LCAT scores and laryngeal-specific hypervigilance or anxiety sub-scores were similar between the GER+ and GER− groups [total: 33.1 (12.6) vs. 32.9 (13.8), p = 0.91; symptom-specific anxiety: 17.8 (9.1) vs. 18.0 (9.6), p = 0.87; and hypervigilance: 15.3 (4.8) vs. 14.8 (5.1), p = 0.56] (Figure 2). An elevated LCAT was similarly distributed between the GER+ and GER− groups (38 (55%) vs. 35 (58%); p = 0.71).
TABLE 2.
Baseline demographic in patients with and without GER+.
| Overall (n = 129) | GER− (n = 60) | GER+ (n = 69) | p-value | |
|---|---|---|---|---|
|
| ||||
| Age (years) | 54.1 (17.5) | 53.3 (18.3) | 54.8 (16.8) | 0.63 |
| Sex (female) | 84/128 (66%) | 42 (70%) | 42/68 (62%) | 0.33 |
| BMI (kg/m2) | 27.6 (6.8) | 25.5 (5.9) | 29.4 (7.0) | <0.01 |
| Race (n = 137) | ||||
| Caucasian | 84 (66%) | 41 (68%) | 43 (62%) | 0.15 |
| African American | 5 (4%) | 4 (7%) | 1 (1%) | |
| Asian | 8 (6%) | 4 (7%) | 4 (6%) | |
| Hispanic | 17 (13%) | 8 (13%) | 9 (13%) | |
| Native American | 0 (0%) | 0 (0%) | 0 (0%) | |
| Unknown/other | 15 (12%) | 3 (5%) | 12 (17%) | |
| Total LCAT | 33.0 (13.1) | 32.9 (13.8) | 33.1 (12.6) | 0.91 |
| LCAT symptom-specific anxiety | 17.9 (9.2) | 18.0 (9.6) | 17.8 (9.1) | 0.87 |
| LCAT hypervigilance | 15.1 (4.9) | 14.8 (5.1) | 15.3 (4.8) | 0.56 |
| Elevated LCAT ≥33 | 73 (57%) | 35 (58%) | 38 (55%) | 0.71 |
| PROMIS anxiety, n = 127 | 17.2 (7.4) | 17.5 (7.6) | 16.9 (7.3) | 0.61 |
| PROMIS anxiety ≥20 (moderate/severe anxiety) | 49/127 (39%) | 26 (43%) | 23/67 (34%) | 0.30 |
| PROMIS depression, n = 126 | 14.8 (7.6) | 15.5 (7.6) | 14.2 (7.6) | 0.33 |
| PROMIS depression >22 (moderate/severe depression) | 24/126 (19%) | 13/60 (22%) | 11/66 (17%) | 0.48 |
| ICQ helplessness | 11.2 (4.3) | 11.3 (4.0) | 11.1 (4.6) | 0.75 |
| ICQ acceptance | 15.2 (3.9) | 14.8 (4.0) | 15.5 (3.9) | 0.32 |
| ICQ perceived benefits | 12.6 (4.7) | 12.7 (4.8) | 12.5 (4.7) | 0.85 |
| NEQOL, n = 128 | 31.7 (14.5) | 31.2 (14.3) | 32.2 (14.8) | 0.71 |
| VHI, n = 125 | 22.4 (25.5) | 21.5 (23.1) | 23.1 (27.5) | 0.73 |
| RSI, n = 126 | 21.8 (10.4) | 20.9 (10.5) | 22.6 (10.2) | 0.34 |
| GerdQ | 8.9 (2.8) | 8.2 (2.7) | 9.6 (2.7) | <0.01 |
| AET prolonged wireless pH monitoring off PPI, n = 77 | 8.2 (7.9) | 2.5 (2.0) n = 30 | 11.9 (8.1) n=47 | <0.01 |
| AET PHI off PPI, n=42 | 3.3 (4.4) | 1.7 (1.7) n = 31 | 8.0 (6.3) n = 11 | <0.01 |
FIGURE 2.
Boxplots comparing total laryngeal cognitive affective tool (LCAT), LCAT symptom-specific anxiety sub-score, and LCAT hypervigilance sub-scores in GER+ and GER− patients.
PRO scores were similar between the GER+ and GER− groups (ICQ helplessness: 11.1 (4.6) vs. 11.3 (4.0), p = 0.75; ICQ acceptance: 15.5 (3.9) vs. 14.8 (4.0), p = 0.32; ICQ perceived benefits: 12.5 (4.7) vs. 12.7 (4.8), p = 0.85; NEQOL: 32.2 (14.8) vs. 31.2 (14.3), p = 0.71; VHI: 23.1 (27.5) vs. 21.5 (23.1), p = 0.73; RSI: 22.6 (10.2) vs. 20.9 (10.5), p = 0.34). GER+ patients reported higher GerdQ scores compared to GER− patients (9.6 (2.7) vs. 8.2 (2.7), p < 0.01).
4 |. DISCUSSION
Patients with chronic LPS represent both diagnostic and therapeutic challenges due to overlapping and multifactorial disease processes. Though literature is limited, studies suggest that these patients often experience impaired QOL, heightened levels of hypervigilance and symptom-specific anxiety, and higher rates of anxiety and depression.8 Up until recent validation of the LCAT score, a questionnaire to assess hypervigilance and symptom-specific anxiety surrounding LPS did not exist. In this study, we assessed patients with chronic LPS to determine the prevalence of increased laryngeal hypervigilance and symptom-specific anxiety, as measured by the LCAT score, as well as rates of anxiety and depression. In addition, we evaluated whether presence/absence of pathologic GERD has any implications on PROs. We found that in patients with chronic LPS: (1) LCAT scores are elevated in 57%; (2) moderate-to-severe anxiety was present in 39% and moderate-to-severe depression in 19%; (3) an elevated LCAT alone or with either moderate-to-severe anxiety/depression was found in 58%; and (4) PRO scores were similar between patients with and without GERD. These results highlight that cognitive-affective constructs may contribute to a patient’s symptom burden, and that therapies targeting these processes are of critical importance.
This concept of psychosocial impairment is well-accepted in typical GERD with studies to date demonstrating significant QOL impairment, anxiety, hypervigilance, and depression in patients, regardless of the presence of physiological reflux.22 The cognitive-affective contribution to esophageal symptom burden continues to evolve as a recent study reported a bidirectional relationship in which patients with GERD more likely to develop anxiety and depression, as well as patients with anxiety and depression are more likely to develop GERD.23 The most recent GERD guidelines provide guidance on therapies targeting the gut-brain axis, such as hypnotherapy, cognitive behavioral therapy, diaphragmatic breathing, relaxation strategies, and neuromodulation.24 However, in regards to patients with chronic LPS, research into QOL and psychosocial impact is much more limited, which has had significant implications on how to properly manage these patients.
Few prior studies have investigated the impact of psychosocial factors, specifically hypervigilance and symptom-specific anxiety in patients with chronic LPS. Wong et al. studied the role of hypervigilance and symptom-specific anxiety in patients with chronic LPS by comparing RSI, GerdQ, and EHAS scores in patients with predominant chronic LPS, predominant chronic GERD symptoms, patients with both chronic GERD symptoms and LPS, and controls. Patients also underwent EGD or 24 h pH-impedance monitoring for assessment of reflux burden. The authors found that patients with concomitant GERD and chronic LPS had higher EHAS scores compared to those with chronic GERD symptoms or controls. In addition, patients with chronic LPS had higher EHAS than controls. EHAS was also found to correlate with RSI scores. There were no significant differences in physiological metrics—including acid reflux burden, esophageal mucosal integrity, and esophageal clearance—among the groups.10 In another study, Wong et al. analyzed patients with typical GERD symptoms with or without concomitant LPS and found that depression and sleep disturbance were significantly higher in patients with typical GERD symptoms with concomitant LPS when compared to patients with isolated GERD symptoms. Anxiety, while not significant, was higher among patients with typical GERD symptoms with concomitant LPS when compared to patients with isolated GERD symptoms. In addition, patients with overlapping GERD and LPS had significantly higher rates of combined psychological distress, irritable bowel syndrome, functional dyspepsia, symptom burden and erosive esophagitis.11 In a separate but similar study, the authors evaluated a population of patients with chronic LPS with or without pathologic GERD and found no significant difference in EHAS scores between the groups.9 These studies suggest that patients with chronic LPS experience increased levels of hypervigilance and symptom-specific anxiety regardless of the presence of pathologic GERD. Though these studies are important, they are limited by the lack of a validated questionnaire to assess laryngeal hypervigilance and symptom-specific anxiety. This study provides additional value by utilizing the laryngeal-specific LCAT and confirms prior hypotheses. Additionally, the elevated levels of anxiety and depression, regardless of reflux physiology, suggests that the perception of the disease is just as impactful on the experience of the disease as the physiological burden itself, and that the modulation of symptom burden derives from a combination physiological and psychological factors, as seen in recent studies on typical GERD.24
These findings emphasize that some patients with chronic LPS may not benefit from reflux-targeted therapies alone and incorporation of multifactorial treatment methods are needed to effectively treat these patients. In general, patients with LPS undergoing evaluation for LPRD may have (1) +GERD/LPRD, (2) +GERD however no LPRD, (3) no GERD or LPRD.25 In all three circumstances, patients may have an overlap of cognitive-affective processes driving LPS, highlighting a key therapeutic target and the importance of multimodal treatment strategies. A recent study utilizing bidirectional Mendelian randomization suggested a bidirectional interplay between physiological and psychological processes in GERD.23 The mechanism of action is theorized to stem from the gut–brain axis with increased psychological perseveration leading to amplification of the autonomic nervous system both peripherally and centrally causing elevated neuronal hypersensitivity and pain processing in the brain.26,27 This activation of the sympathetic nervous system also initiates a systemic stress response which itself can influence symptom perception and modulate the experience of refluxate,22 which may in turn cycle back to worsen the initial inciting anxiety and hypervigilance. Understanding of this complex, cyclic interaction between laryngeal thoughts, feelings, behaviors and reflux burden leading to LPRD continues to evolve, without clear identification of the initial inciting event—psychological, physiological, or mechanical, and this area is ripe for future investigation. Even without this knowledge, integrating behavioral modifications through voice-directed treatments, cognitive behavioral therapies, or additional medical interventions targeting stress reduction and psychological distress is crucial in improving the treatment outcomes and breaking this maladaptive cycle of perpetuated disease burden in patients with chronic LPS.
Strengths of the study include that patients were well-characterized with both reflux monitoring data, symptoms, and eight validated questionnaires evaluating, not only symptoms, but also QOL, depression, and anxiety. These questionnaires include the LCAT, a newly validated instrument that specifically measures laryngeal hypervigilance and symptom-specific anxiety.
Limitations include the single-center study design, which limits generalizability to other populations and the lack of outcomes data. EHAS scores were also not collected and therefore, differences between LCAT and EHAS scores in patients with and without concomitant esophageal symptoms could not be assessed. Additionally, due to the lack of a diagnostic gold standard for LPRD, findings on reflux monitoring and EGD were utilized to diagnose GER+ per the AGA Clinical Practice Update on Extra-esophageal Reflux which recommends either 24-h pH impedance monitoring or prolonged wireless pH monitoring.28 While some clinicians suggest utilizing hypopharyngeal—esophageal multichannel intraluminal impedance-pH monitoring to evaluate for LPRD, this is not our standard practice given poor correlation with extra-esophageal symptoms and proximal reflux, low interobserver agreement over these proximal reflux events, and variation in normative values for hypopharyngeal events.29 Nonetheless, the lack of a diagnostic tool to measure burden of esophagopharyngeal reflux remains a study limitation.
5 |. CONCLUSION
In conclusion, this study highlights that patients with chronic LPS experience heightened levels of hypervigilance, laryngeal symptom-specific anxiety, anxiety, and depression, regardless of the presence of pathologic GERD. These findings suggest that therapies targeting cognitive-affective processes and hyper-responsive laryngeal behaviors are an essential component of treatment as nearly all are modifiable and can significantly improve patient symptoms and QOL. Future studies are needed to evaluate how multimodal therapeutic and behavioral interventions can improve patient outcomes and overall well-being.
Key points.
Patients with chronic laryngopharyngeal symptoms experience high rates of hypervigilance, symptom-specific anxiety, anxiety and depression, regardless of whether pathologic GERD is present.
Cognitive-affective processes represent a potential target for treatment to help improve patient symptoms and quality of life.
Future studies are needed to assess whether behavioral and multidisciplinary treatments can improve symptoms in patients with chronic laryngopharyngeal symptoms.
FUNDING INFORMATION
NIH grant T32 DK007202; NIH DK125266 (Yadlapati, PI); NIH DK135513 (Yadlapati, PI); University of California San Diego Academic Senate Grant P025945. The project described was partially supported by the National Institutes of Health, Grant UL1TR001442. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Footnotes
CONFLICT OF INTEREST STATEMENT
KL, AJK, MG, EW: No Disclosures. TT: Abyle Health (Consultant, Advisory Board), Takeda (Consultant), Healthline (Consultant). RY: Consultant for Medtronic, Phathom Pharmaceuticals, StatLinkMD, Reckitt Benckiser Healthcare Ltd, Medscape; Research Support: Ironwood Pharmaceuticals; Advisory Board with Stock Options: RJS Mediagnostix.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.