Laryngopharyngeal Symptoms and Laryngopharyngeal Reflux Disease: Presentation, Health Care Burden, and Risk Stratification

Abstract

Background:

Throat and airway symptoms are common, but only a small proportion are reflux-related. The term “laryngopharyngeal reflux” has variable definitions in the literature and has been used to describe symptomatic patients with or without objective reflux, often leading to prolonged/unnecessary treatment trials.

Purpose:

The San Diego consensus introduced the term laryngopharyngeal symptoms (LPS) to describe upper aerodigestive symptoms with potential relationship to reflux physiology, including cough, regurgitation, throat pain, throat clearing, excess phlegm, and hoarseness/voice change. This review describes presentation, health care burden and risk stratification of throat and airway symptoms in light of the San Diego consensus definitions and clinical approach. Laryngopharyngeal reflux disease (LPRD) requires objective evidence of pathologic reflux in addition to LPS. Importantly, LPS alone do not predict LPRD. While various validated patient-reported outcome instruments are available, only some are LPS/LPRD-specific, and all lack specificity for making a diagnosis of LPRD. These instruments may have value in tracking symptoms over time and post-treatment. Concurrent typical reflux symptoms may prompt empiric anti-reflux medication trials as initial therapy. Risk stratification scores have been developed for the purpose of directing upfront therapy for high-risk patients and investigation for intermediate/low-risk patients, but their clinical use needs further validation. Objective diagnosis of LPRD provides confidence in escalation of reflux interventions. Life-threatening long-term sequelae are infrequent in LPS/LPRD, although impact on quality of life and healthcare burden can be profound.

1 |. Introduction

The term “laryngopharyngeal reflux (LPR),” introduced in the early 1990s to describe bothersome potentially reflux-related throat and airway symptoms [1, 2], does not have a finite and universally accepted definition. The implication of reflux in the term has led to prolonged or unnecessary anti-reflux therapies, even though objective pathologic reflux is often absent in these patients. There is a significant impact of these ‘LPR’ symptoms on quality of life [3, 4] and rising health care costs [5, 6].

Given the poor specificity of the term LPR for objective reflux-based pathophysiology, there was an urgent need to better define upper aerodigestive symptoms and identify patients where objective reflux is confirmed. The San Diego consensus gathered a 14-member multinational team of gastroenterologists, otolaryngologists, speech and language pathologists and clinical psychologists to develop guidance on evaluation and approach to upper aerodigestive symptoms [7]. Six subgroups were formed, focusing on definition/terminology, evaluation and risk stratification, reflux monitoring, therapeutic trials, behavioral factors and therapy. Each subgroup performed a literature review and developed statements, which were subsequently voted upon by a 28-member voting panel that included the core group. The RAND Appropriateness Method (RAM) was utilized to determine appropriateness of statements, which required ≥ 80% agreement among the voting members. This series of three technical reviews expand in detail the literature underlying the San Diego consensus statements [7]. The current review focuses on descriptions of terminology, presentation, risk stratification and prognosis of patients presenting with upper aerodigestive symptoms potentially related to a reflux-based mechanism. Two subsequent reviews will discuss diagnostic testing/clinical approach and management/interdisciplinary considerations.

2 |. Laryngopharyngeal Symptoms

The distinction of evidence-based potential relationships rather than the presumptive relationship to gastroesophageal reflux suggested by “LPR” is critical for better patient assessment and management, and for avoiding unnecessary and prolonged use of acid suppressants when no potential relationship exists. The San Diego consensus initiated collaborative discussion among the multinational interdisciplinary team to develop representative terminology for use in clinical care and in research. Since these patients often present to one or more specialists, agreement between gastroenterologists, otolaryngologists, speech pathologists and psychologists in the consensus panel was actively sought [7]. The panel unanimously decided on the term laryngopharyngeal symptoms (LPS) to refer to throat and upper airway symptoms with a potential relationship to gastroesophageal reflux [7]. To qualify as LPS, the presenting symptoms must be chronic (i.e., occur over 8 weeks or more), occur frequently (i.e., at least twice weekly), and affect the throat or upper airways, as informed by systematic, narrative and expert reviews [8–10]. In contrast, the term laryngopharyngeal reflux disease (LPRD) requires both LPS and objective evidence of gastroesophageal reflux (Figure 1) [7].

FIGURE 1 |.

Overview of risk stratification and assessment of laryngopharyngeal symptoms (LPS) with potential for reflux etiology. Evaluation should start with laryngoscopy to rule out other ear, nose, and throat (ENT) causes of symptoms. Patient-reported outcome instruments may quantify symptom severity and allow longitudinal follow-up of symptoms over time, but they are not diagnostic of laryngopharyngeal reflux disease (LPRD). Further risk stratification involves evaluation for presence or absence of concurrent typical esophageal symptoms of reflux. Empiric acid suppression ± alginate therapy may be considered for those with typical symptoms, while upfront esophageal testing for objective evidence of reflux should be performed to direct therapy for patients with isolated LPS. Evaluation and treatment for hyperresponsiveness and hypervigilance may also be considered while awaiting investigation. Testing modalities include upper endoscopy and/or ambulatory reflux monitoring (wireless pH monitoring, pH-impedance monitoring, hypopharyngeal-esophageal multichannel intraluminal impedance-pH monitoring), which identify objective reflux in ~1/3 of patients presenting with LPS.

To find agreement for which symptoms have potential for a relationship to reflux, a collection of symptoms frequently identified in the literature as part of ‘LPR’ were pooled [2, 11]. Symptoms meeting consensus for inclusion under the LPS umbrella include cough (89% agreement in the San Diego consensus), regurgitation (89%), throat pain/sore throat (89%), throat clearing (86%), excess phlegm (82%), and hoarseness/voice change (80%) (Figure 1). Symptoms that did not reach consensus consisted of tongue burning, nasal burning, post-nasal drip, halitosis, and dysphagia, primarily based on low likelihood of relationship to reflux of gastric content. Of note, globus (75% agreement) approached but did not reach consensus as an LPS, primarily because it is often a negative predictor of reflux physiology [12–14] and is linked to visceral hypersensitivity [13, 15]. Frequent belching (54% agreement) was excluded from the LPS set as it may not always directly associate with liquid refluxate, especially when escape of air from the esophagus is part of supragastric belching, which is considered a disorder of gut-brain interaction (DGBI) when excessive [16, 17]. A gastric belch during transient lower esophageal sphincter (LES) relaxation can coexist with reflux events, but other reflux symptoms are often present and are more predictive of reflux disease than the belch itself [18].

LPS can occur with or without typical reflux symptoms of heartburn, regurgitation or esophageal chest pain [19]. Successful treatment of reflux-related LPS is more likely in patients with concurrent typical reflux symptoms [20]. Overall, the proportion of patients with LPS related to gastroesophageal reflux (LPRD) is lower than that for typical reflux symptoms [21].

The presence of LPS does not implicate gastroesophageal reflux as the origin of symptoms, and consideration of other factors and careful interpretation are required [22]. A process for differential diagnosis is essential as LPS do not always have a singular cause, and non-reflux etiologies are often more important or concurrent mechanisms. For example, chronic cough may relate to allergies, medication side effects, airway conditions, asthma or neurogenic process rather than or in addition to gastroesophageal reflux [23]. Chronic cough assessed in a study of 28 patients with no prior diagnosis or treatment for reflux required careful validated symptom assessments, laryngoscopy, pulmonary function tests, serology testing, esophageal manometry and reflux monitoring [24]. Most patients had additional risk factors (asthma, allergic rhinitis, medications causing cough), highlighting the multifactorial etiology of cough and other LPS. Patients who responded to reflux treatments had higher number of upright and long duration reflux events, while those with vocal cord motion abnormalities such as vocal fold paresis (seen in 64%), were significantly less likely to respond to reflux medication [24]. In another approach, a predictive score (COuGH RefluX score) was developed using six weighted factors, Cough, Overweight/obesity, Globus, Hiatus hernia, Regurgitation and male seX to evaluate the likelihood of increased reflux burden in patients with LPS [25]. Of these, three elements (obesity, regurgitation, hiatal hernia) are common in patients with typical reflux symptoms, indicating that their overlap with LPS might predict a higher likelihood of GERD.

2.1 |. Epidemiology and Health Care Burden of LPS

LPS are among the most common atypical GERD symptoms in the general population, whether isolated, or overlapping with typical GERD symptoms [26]. As many as 10%–35% of the general population across the world report chronic LPS in population studies [27–29]. In a survey from Olmsted County, MN, almost 15% reported hoarseness, including 23.4% of patients who also reported frequent GERD symptoms, and 15.4% with infrequent GERD symptoms; 10.7% had isolated hoarseness [26]. In a study of 300 Korean patients with GERD symptoms, as many as 50% also had LPS [3]. In a sampling of 378 patients attending primary care practices in the United Kingdom, 34.4% had reflux symptom index (RSI) score > 10, with highest prevalence in the 40–60 year age group, and 74.3% with significant typical symptoms (vs. 18.2% with low GERD score) also reporting LPS [27]. As many as 38.5% of 340 randomly selected patients from a general Greek population reported voice disorders, and 18.8% had RSI score > 13 [28]. Finally, in a large multicenter cross-sectional survey of > 90,000 eligible outpatients in China, 10% had LPS, with higher prevalence in males and older individuals [29].

Patients with LPS seek care from various health-care providers including primary care physicians, otolaryngologists, gastroenterologists, and surgeons [5], each of whom brings their own perspective on evaluation and management. In a survey of 314 physicians of which > 90% were primary care providers, 64% were likely to treat LPS with acid suppressants at first presentation despite lack of evidence for reflux disease [30]. While almost all survey respondents considered referral of any LPS patient to an otolaryngologist [30], further evaluation typically comprises an average of 10 specialist consultations and 6 diagnostic tests [5]. When seen by an otolaryngologist, laryngoscopy is typically the first diagnostic test. While laryngoscopy is indicated to evaluate for alternate disorders, it often results in a diagnosis of LPRD and a PPI prescription based on non-specific findings of infraglottic or post-cricoid erythema/edema, and interarytenoid mucosal hypertrophy, findings commonly seen in non-LPRD states as well as healthy individuals [31]. When evaluated by a gastroenterologist, endoscopy is often performed, which carries a yield of conclusive GERD evidence in < 15%, leaving the patient with no conclusive GERD evidence in limbo and potentially on PPI therapy [32]. A surgeon evaluating an LPS patient might consider antireflux surgery, but LPS outcomes are suboptimal [33, 34], especially if performed in patients with symptom quantification alone without objective GERD evidence [35]. The 5-year cost of managing LPS was estimated to be $13,700 USD per patient [6], contributing to annual health care costs that exceed $50 billion, 5.4 times higher than that for typical GERD [5]. Much of the health care expenditure stems from continued and prolonged PPI administration, often prescribed as double dose twice daily, despite the fact that LPS respond poorly to these agents.

2.2 |. Risk Stratification of LPS

LPS are significantly more prevalent than LPRD, especially isolated LPS without concurrent typical esophageal symptoms. The objective of risk stratification is to identify and preselect patients with LPS with LPRD for specific reflux management, and to offer alternative options for symptom control in patients without LPRD.

2.2.1 |. Symptoms

Identifying patients with LPS with potential for LPRD based only on presentation lacks specificity. A cohort study of 133 adults found that LPS symptoms of hoarseness, mucus in throat, throat clearing, and cough did not correlate with objective pharyngeal reflux using a combined hypopharyngeal-esophageal multichannel intraluminal impedance and pH (HEMII-pH) catheter [36]. In a principal component analysis of multiple clinical and testing data in 302 patients with LPS from three tertiary care centers, only a third had clinical evidence supporting LPRD, while the remainder had symptoms without objective findings [37]. Five phenotypes were identified, of which only two had features of GERD. Other studies have demonstrated globus to be a negative predictor of objective reflux evidence on testing [38]. Thus, while characterizing symptoms is of value, symptoms alone do not diagnose LPRD, since LPS represent multiple underlying mechanisms of which reflux is just one.

2.2.2 |. Patient Reported Outcome Instruments

Although several validated patient reported outcome (PRO) instruments are available for characterization of upper aerodigestive and esophageal symptoms (Table 1), none are specific enough for a definitive diagnosis of LPRD, and most do not predict abnormal reflux on testing or symptom outcome following reflux management. The best use of these PRO instruments is in quantifying and monitoring symptoms at baseline and over time, especially after therapy [7].

TABLE 1 |.

Patient-reported outcome instruments in LPS.

Instrument	Characteristics	Primary Use	Performance characteristics in identifying LPRD	Validation	Comments
Symptoms	Descriptive	Describes LPS	Low
RSI	9-item questionnaire validated for LPS; 1 month recall; Abnormal when ≥ 13	Quantifies symptom burden; tracks burden over time and with treatment	Sensitive for symptom detection, low specificity for LPRD	Validated for reflux testing metrics (cross-sectional) and treatment outcome to reflux therapy (prospective)	Typical symptoms of heartburn and regurgitation are included
RSS	9-item questionnaire validated using HEMII-pH data	Predicts abnormal proximal or pharyngeal reflux	Higher sensitivity and specificity compared to RSI	Validated for reflux testing metrics (cross-sectional) and treatment outcome to reflux therapy (prospective)	Incomplete as a standalone tool to diagnose LPRD
LPR-HRQL	43-item questionnaire	Evaluates impact of LPS on quality of life; tracks treatment response	Not sensitive or specific for LPRD	Validated for treatment outcome and quality of life (prospective)	Does not provide LPRD diagnosis but quantifies quality of life
VHI, LCQ, CSI	Non-LPRD-specific voice and cough instruments	Evaluate voice and cough related morbidity	Sensitive for symptom quantification	Validated for treatment outcome of specific symptoms (prospective)	Do not provide LPRD diagnosis
GERDQ	6-item questionnaire, 1 week recall; abnormal when ≥ 8	Quantifies typical GERD symptoms	Modest sensitivity and specificity for GERD but not LPRD	Validated for reflux testing metrics (cross-sectional) and treatment outcome to reflux therapy (prospective)	Useful for identification and quantification of typical GERD symptoms
GERD-HRQL	10-item questionnaire, abnormal when > 12	Assesses impact of typical GERD symptoms on quality of life	Does not identify LPRD	Validated for reflux testing metrics (cross-sectional) and treatment outcome to reflux therapy (prospective)	Useful to assess impact of typical symptoms on quality of life
GSS	100-mm visual analog scale, 2 week recall	Quantifies global esophageal symptoms; tracks symptom burden over time	Modest sensitivity and specificity for GERD	Validated for reflux testing metrics (cross-sectional) and treatment outcome to reflux therapy (prospective)	Not enough data on predicting LPRD
DSI	Product of symptom severity and frequency assessed using 5-point Likert scales; 2 week recall	Identifies and quantifies dominant symptom; tracks symptom burden over time	Modest sensitivity and specificity for GERD, Not validated for LPRD	Validated for reflux testing metrics (cross-sectional)	Not enough data on predicting LPRD

Abbreviations: CSI, cough severity index; DSI, dominant symptom intensity; GERD, gastroesophageal reflux disease; GERDQ, GERD questionnaire; GSS, global symptom severity; HEMII-pH, hypopharyngeal-esophageal multichannel intraluminal impedance and pH; LCQ, Leicester cough questionnaire; LPRD, laryngopharyngeal reflux disease; LPR-HRQL, laryngopharyngeal reflux health-related quality of life; LPS, laryngopharyngeal symptoms; RSI, reflux symptom index; RSS, reflux symptom score; VHI, voice handicap index.

The RSI is a 9-item symptom questionnaire validated for quantification of LPS potentially related to reflux [39], although individual evaluated symptoms are non-specific and include typical esophageal symptoms of heartburn and regurgitation. While a score > 12 is considered abnormal, it does not identify patients with abnormal pharyngeal reflux or correlate with symptoms during HEMII-pH testing [40, 41]. The 9-item Reflux Symptom Score (RSS) was developed using data from HEMII-pH, and has better performance characteristics in predicting abnormal proximal esophageal or pharyngeal reflux [42, 43]; however, even this score is not adequate as a standalone tool for a conclusive LPRD diagnosis. The LPR-Health Related Quality of Life (LPR-HRQL) is a 43-item questionnaire that evaluates the impact of LPS on quality of life but does not provide LPRD diagnosis [44]. Other validated instruments include the Voice Handicap Index-10 (VHI) [45], Leicester Cough Questionnaire (LCQ) [46], and the Cough Severity Index (CSI) [47], which quantify symptoms but do not provide diagnostic or risk-stratification value.

Since LPS can overlap with typical GERD symptoms, GERDQ and GERD health related quality of life (GERD-HRQL) can be useful in defining esophageal symptoms and related quality of life. The 6-item GERDQ is a validated questionnaire used for characterizing typical GERD symptoms, where a score of > 8 is considered elevated [48, 49]. The GERD-HRQL is a 10-question instrument that evaluates typical reflux symptoms, with each score ranging from 0 to 5 based on frequency and impact on quality of life; a score > 12 is considered abnormal [50]. The Global Symptom Severity (GSS) requires patients to mark their overall symptomatic state over the previous 2 weeks on a 100-mm visual analog scale anchored by no symptoms and severe symptoms [51]. This is often used in conjunction with Dominant Symptom Intensity (DSI) [52], the product of symptom severity and frequency on 5-point Likert scales. Both have been validated for use with reflux symptoms including LPS, but additional research is needed to determine relationship to LPRD. Similar to LPS instruments, these instruments are not specific for a conclusive GERD/LPRD diagnosis.

2.2.3 |. Scoring Systems

The Reflux Finding Score (RFS) and Reflux Sign Assessment (RSA) are two scoring symptoms developed for use during laryngoscopic evaluation of the upper airway. However, these scores have been shown to have suboptimal specificity [53–55] and significant interobserver variability [31, 56] even among expert otolaryngologists [7]. Nevertheless, laryngoscopy is an important initial step in the evaluation of LPS to identify non-reflux etiologies.

The COuGH RefluX score stratifies patients with LPS into low, medium or high likelihood of reflux [38]. The score was developed from an international cohort of 856 patients with LPS and demonstrated ~80% sensitivity and specificity for proven GERD based on Lyon Consensus criteria and for proximal esophageal/pharyngeal reflux on HEMII-pH [57]. Follow-u p studies have demonstrated that PPI response is highest in patients with high likelihood scores, where an empiric PPI trial could be considered. On the other hand, low likelihood scores can prompt consideration of non-reflux mechanisms for LPS, while medium likelihood scores require upfront reflux evaluation [58]. While this score shows potential as a risk stratification tool, it relies on testing data to detect the presence of hiatal hernia and is therefore not a pure clinical score. Moreover, the score was developed and initially validated in tertiary gastroenterology referral centers specializing in LPS/LPRD, which may limit generalizability to other practice or specialty (e.g., otolaryngology) settings. Further outcome and validation studies in different practice environments are needed for better positioning in clinical management.

The Heartburn, Asthma, and Body mass index in Extra-Esophageal Reflux (HAs-BEER) score was developed as a clinical decision-making tool that estimates pretest probability of abnormal reflux in patients with atypical reflux presentations by evaluating presence or absence of typical symptoms (heartburn) and assessing risk factors for GERD (obesity, hiatus hernia), in addition to atypical symptoms of asthma/wheezing, cough and hoarseness [59]. A score of ≤ 2 indicates low likelihood of significant reflux with a negative predictive value of 85%, where up-front reflux monitoring would be indicated to evaluate for abnormal reflux burden. However, < 10% of the combined derivation and validation cohort from the initial report had an abnormal score (3), limiting the discriminatory value to a small subset of patients. Importantly, there has been no further published study or validation beyond the initial report of the score.

2.2.4 |. Empiric Trials of PPI

While empiric PPI trials are extensively utilized in clinical practice, response is lower in LPS compared to typical reflux symptoms, in addition to the fact that LPS may be less sensitive to acid suppression [60, 61]. A multicenter, randomized placebo-controlled trial of 262 patients with various LPS quantified using RSI demonstrated no difference in RSI change between patients treated with lansoprazole 30 mg twice a day or placebo at 4 and 12 months [62]. Considering data from available randomized controlled trials evaluating PPI therapy in LPS, the number needed to treat for a response (NNT) is 25 in patients with chronic cough, and 78 to > 100 with hoarseness [63, 64]. In contrast, NNT is typically lower with typical symptoms, < 5 for heartburn and < 6 for regurgitation. If cough patients with objective GERD on esophageal testing are selectively analyzed for PPI response, NNT becomes similar to that for typical symptoms (4.2), indicating that symptoms alone are not predictive of PPI response or GERD, but up-front objective testing can identify patients with LPS who could respond to PPI [7, 64].

2.2.5 |. Empiric Trials of Alginate

Alginates form a raft or barrier that floats over gastric contents, in addition to creating a protective coating on the esophageal and upper aerodigestive tract mucosa. The expected benefits include reducing contact of gastric fluid with sensitive upper aerodigestive tract mucosa and lowering reflux episodes, especially while recumbent. Alginates were demonstrated to be non-inferior to PPIs in reducing RSI and RFS in patients with LPS in a randomized controlled trial [65]. Among 49 patients randomized to alginate or no treatment in an open label parallel group study, 24 patients receiving alginate four times a day had significantly lower RSI scores at 2 and 6 months, and lower RFS scores at 6 months compared to controls [66]. A systematic review that included 16 studies found that alginates had benefit both as monotherapy and in combination with PPI, but the dose, frequency of administration, duration of therapy and optimal symptom pattern for alginate use could not be conclusively determined [67]. Alginates have also been used as short-term therapy and while tapering PPIs in patients with LPS [68]. These findings suggest that empiric alginates can be of value in selected patients with LPS, but response or lack thereof does not predict presence or absence of LPRD.

3 |. Laryngopharyngeal Reflux Disease

Limiting use of the term LPRD to patients with conclusive evidence of gastroesophageal reflux is critical to targeted reflux-based therapy and improving treatment outcomes. Reflux burden can be assessed in patients with LPS using endoscopy and either of pH-impedance monitoring, hypopharyngeal-esophageal multichannel intraluminal impedance-pH (HEMII-pH) monitoring, and prolonged wireless pH monitoring (Figure 1), which are discussed further in a subsequent technical review in this series. High resolution manometry evaluates esophageal peristaltic function and esophagogastric junction (EGJ) morphology. Traditionally, objective evidence of reflux consists of Los Angeles Grade B, C, or D esophagitis or biopsy-proven Barrett's esophagus on upper endoscopy, and/or abnormal findings of ambulatory reflux monitoring according to Lyon consensus 2.0 [69–72]. Adjunctive findings supporting gastroesophageal reflux include a disrupted EGJ (hypotensive LES, hiatus hernia), impaired esophageal clearance (ineffective esophageal motility, absent contractility), reflux-symptom association, high reflux episode counts, and disruption of esophageal mucosal integrity measured using baseline impedance [70]. However, even objective reflux evidence does not always imply causality of LPS, and evidence supporting an etiologic relationship between gastroesophageal reflux and LPS is paramount prior to invasive anti-reflux management [7].

Objective GERD-based phenotypes of LPS fulfilling LPRD criteria account for a third of all patients with LPS presenting for evaluation [37], but only a small proportion will demonstrate esophageal mucosal injury on upper endoscopy. In a multicenter study of 756 patients undergoing esophageal evaluation for LPS, endoscopic evidence of erosive esophagitis (LA B or higher) was found in 7.4%, with higher rates in LPS with concurrent typical symptoms (8.9%) compared to isolated LPS (3.4%) [32]. Barrett's esophagus was diagnosed in 3.3%, and peptic stricture in 1.5%. Although these are substantially lower than the likelihood of endoscopic erosive findings in patients with typical symptoms [73], upper endoscopy can also identify hiatus hernia, and help rule out alternate esophageal mucosal processes.

Both prolonged wireless reflux monitoring and catheter-based pH/pH-impedance monitoring have been utilized for evaluation of reflux evidence in LPS. Wireless pH monitoring assesses distal esophageal acid exposure over multiple days, providing data that could be useful prior to planning invasive reflux management [7]. However, acidic and weakly/non-acidic reflux events may both be relevant in LPS. Impedance-based reflux monitoring can provide objective counts of all reflux events while also recording distal acid exposure time and baseline impedance, and the number, proximal migration and duration of reflux events may be important determinants of LPS [74]. pH-impedance monitoring can also determine if episodic LPS such as cough preceded reflux (i.e., cough-induced reflux) or if reflux triggered cough (i.e., reflux-induced cough), especially if an acoustic monitor is used to identify cough episodes [75, 76]. Thus, pH-impedance monitoring may define the mechanism of LPS in patients with episodic symptoms such as cough and throat clearing. However, precise thresholds of reflux episode counts on proximal esophageal pH-impedance monitoring that predict response to reflux management remain unclear. Oropharyngeal pH testing alone has poor specificity and is subject to drying artifact of the oropharyngeal pH sensor, and is not recommended [7].

In a prospective cohort of 196 patients with LPS evaluated in Taiwan, only 11.2% had proven GERD according to Lyon criteria on pH-impedance monitoring, with 15.6% when both LPS and typical symptoms were present and 5.4% in isolated LPS [58]. In a multicenter LPS cohort of 813 patients undergoing reflux monitoring off PPI, 27% had an abnormal pH-impedance study, while 50% had abnormal distal esophageal acid exposure on wireless pH monitoring [77]. Among 15 patients who had both tests, only 40% had concordant findings. In a cohort of 66 patients with both pH-impedance monitoring and prolonged wireless pH monitoring off therapy, discordant findings were noted in 44%, within which almost three-quarters had both LPS and typical symptoms [78]. These findings suggest that the diagnostic yield for LPRD in LPS is lower than in patients with typical reflux symptoms, and that the choice of diagnostic testing may impact the diagnostic yield.

3.1 |. Implications of LPRD Diagnosis

Establishing objective evidence of LPRD with or without typical reflux symptoms informs treatments options and predicts outcome. In a cohort of 25 professional voice users with persistent LPS despite acid suppression who underwent antireflux surgery based on laryngoscopic findings (RFS), there was no change in laryngoscopic findings or RFS before and after surgery [35]. In contrast, in a study of 86 LPRD patients with objective GERD evidence undergoing Toupet fundoplication, significant improvements were noted in individual LPS, RSI and QOL scores at 1 year follow up [79]. Additionally, among 49 LPRD patients with objective GERD evidence undergoing transesophageal incisionless fundoplication, 73% were satisfied with management and 80% were able to discontinue PPI therapy, with similar results in the subset with isolated LPS [80]. Thus, objective GERD evidence driving LPRD diagnosis can provide confidence in recommendations for permanent invasive management for GERD in carefully selected cases [81]. However, surgical intervention for patients with LPS and LPRD generally have worse outcome than patients with typical reflux symptoms with objective GERD evidence, reflecting the multifactorial etiology of LPS [82, 83].

Patients with LPRD as identified by Lyon 2.0 criteria also demonstrate a higher likelihood of response to acid suppressive therapy compared to patients without LPRD [58]. However, response to empirical antireflux medicine can be impacted by factors such as compliance, placebo effect and gender. Multidisciplinary management is advocated, since hyperresponsiveness and hypervigilance can overlap even with objective LPRD, and behavioral approaches including speech/voice therapy, cognitive/behavioral therapy, gut directed hypnotherapy and laryngeal recalibration therapy may need to be considered. Management strategies for LPS/LPRD, including multidisciplinary considerations, are further discussed in a subsequent technical review in this series.

3.1.1 |. Prognosis

An important consequence of LPS and LPRD is impact on quality of life, primarily related to persistent voice dysfunction, cough and throat clearing which affect social functioning [84, 85]. Patients with LPS report high rates of affective disorders such as anxiety and depression [86], lower satisfaction with treatment, and work impairment [3], as well as elevated hypervigilance and symptom specific anxiety [87]. Since patients with LPS have greater impact on quality of life compared to healthy controls, patient education is important to ensure understanding of the multifactorial etiology of LPS and the role of affective disorders and hypervigilance in determining symptom burden [4].

Life-threatening long-term sequelae are infrequent in LPS and LPRD. In a systematic review and meta-analysis of 18 studies, the risk for laryngeal cancer had an odds ratio of 3.09 (95% CI 1.69–5.65) with LPS, similar to that of GERD (odds ratio 2.37, CI 1.79–3.14), regardless of whether the diagnosis of GERD and LPRD was based on objective testing (odds ratio 3.82, CI 2.61–5.59) [88].

4 |. Conclusions

The San Diego Consensus has developed new terminology that allows characterization of LPS without implying reflux as the primary etiology for symptoms, while recognizing that a proportion of LPS will have an etiologic link to gastroesophageal reflux, termed LPRD. A diagnosis of LPRD requires objective evidence of retrograde movement of gastric content and its consequences. Certain risk stratification tools help in initial patient triage, but do not provide conclusive LPRD diagnosis. While criteria developed for GERD continue to be used for identifying objective reflux evidence, specific criteria for LPRD need to be developed.

Key Points.

• Laryngopharyngeal symptoms (LPS) consist of upper aerodigestive symptoms with potential for reflux-based etiology, termed “laryngopharyngeal reflux disease” when objective gastroesophageal reflux is demonstrated.

• As many as 10%–35% of the general population report chronic LPS, with significant impact on quality of life and health care costs.

• Patient reported outcome instruments serve to quantify LPS at baseline and after therapy but are not specific for LPRD.

• Objective gastroesophageal reflux disease is identified in approximately a third of LPS patients presenting for diagnostic evaluation, more often when typical symptoms coexist.

• Life-threatening long-term sequelae are infrequent in LPS and LPRD.

Data Availability Statement

The authors have nothing to report.