Esophageal Baseline Impedance is Associated with Laryngopharyngeal Reflux and Treatment Response.

OBJECTIVE: To evaluate the efficacy of distal esophageal mean nocturnal baseline impedance (MNBI), a general marker of esophageal mucosal barrier integrity, in predicting laryngopharyngeal reflux (LPR) and symptomatic response to acid reflux therapy. METHODS: This retrospective study analyzed 173 patients who presented with symptoms of laryngopharyngeal reflux and underwent 24-h multichannel intraluminal impedance-pH (MII-pH) testing. Mean nocturnal baseline impedance values were calculated and assessed for their association and ability to predict LPR symptoms, MII-pH results, treatment response, and other markers of LPR. RESULTS: Notably, 153 of the 173 patients were tested off acid suppression medication and included in statistical analysis. Based on the MII-pH probe data, 108 (71%) patients had LPR, 8 (5%) had gastroesophageal reflux disease (GERD), and 37 (24%) were without pathologic reflux. Distal esophageal MNBI of LPR patients was significantly lower in LPR patients than patients with negative studies (1332 ± 94.8 vs. 2158 ± 173.5, p = 0.001). Among 118 patients who trialed antireflux therapy, a distal esophageal MNBI cutoff value of <1580 Ω was an independent predictor of treatment response (OR = 4.148 [1.877-9.189]). This value better predicted improvement with antireflux therapy for LPR than other objective MII-pH probe data, which were not independent predictors of treatment response. CONCLUSION: Distal esophageal MNBI values may have value in the diagnosis of LPR and potentially predict medication responsiveness in LPR patients. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Inhaled fosamprenavir for laryngopharyngeal reflux: Toxicology and fluid dynamics modeling.

Objectives: Approximately 25% of Americans suffer from laryngopharyngeal reflux (LPR), a disease for which no effective medical therapy exists. Pepsin is a predominant source of damage during LPR and a key therapeutic target. Fosamprenavir (FOS) inhibits pepsin and prevents damage in an LPR mouse model. Inhaled FOS protects at a lower dose than oral; however, the safety of inhaled FOS is unknown and there are no inhalers for laryngopharyngeal delivery. A pre-Good Lab Practice (GLP) study of inhaled FOS was performed to assess safety and computational fluid dynamics (CFD) modeling used to predict the optimal particle size for a laryngopharyngeal dry powder inhaler (DPI). Methods: Aerosolized FOS, amprenavir (APR), or air (control) were provided 5 days/week for 4 weeks (n = 6) in an LPR mouse model. Organs (nasal cavity, larynx, esophagus, trachea, lung, liver, heart, and kidney) were assessed by a pathologist and bronchoalveolar lavage cytokines and plasma cardiotoxicity markers were assessed by Luminex assay. CFD simulations were conducted in a model of a healthy 49-year-old female. Results: No significant increase was observed in histologic lesions, cytokines, or cardiotoxicity markers in FOS or APR groups relative to the control. CFD predicted that laryngopharyngeal deposition was maximized with aerodynamic diameters of 8.1-11.5 µm for inhalation rates of 30-60 L/min. Conclusions: A 4-week pre-GLP study supports the safety of inhaled FOS. A formal GLP assessment is underway to support a phase I clinical trial of an FOS DPI for LPR. Level of Evidence: NA.

Evaluation of Social Determinants of Health on Dysphagia Care Pathways at a Tertiary Care Facility.

OBJECTIVES: Limited research exists evaluating the impact of social determinants of health in influencing care pathways for patients with dysphagia. A better understanding of whether these determinants correlate to altered care and resource utilization is essential as it relates to patient outcomes. STUDY DESIGN: Retrospective chart review. METHODS: All adult patients seen at a tertiary midwestern hospital were screened for ICD codes of dysphagia diagnoses from 2009 to 2019. Demographic information was collected from these patients with dysphagia including sex, race, ethnicity, and insurance status. Subgroup analysis was performed to assess referral pattern rates and types of diagnostic interventions ordered (none, videofluoroscopic swallow study, esophagram, and esophagogastroduodenoscopy). RESULTS: A total of 31,858 patients with dysphagia were seen at our institution during the study period, with a majority being female (56.36%), Caucasian (79.83%), and publicly insured (63.16%), at a median age of 60.35 years. There were no significant care delivery pattern differences based on geography/zip code analyses. African American patients were significantly more likely to have imaging or interventions performed (odds ratio [OR] 1.463, p = 0.005). Patients with public insurance also had higher rates of diagnostic study utilization (OR 1.53, p = 0.01). Only 3% of all patients with dysphagia were seen by laryngologists. CONCLUSION: No significant differences were seen in dysphagia evaluation modalities based on zip code analyses surrounding this tertiary care facility. African American patients and those with public insurance had significantly higher utilization of subsequent testing and intervention for dysphagia care. Further studies are necessary to delineate causes and outcome differences for these measurable differences in dysphagia care pathways. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:1139-1146, 2024.

The Dubai Definition and Diagnostic Criteria of Laryngopharyngeal Reflux: The IFOS Consensus.

OBJECTIVE: The objective of this work was to gather an international consensus group to propose a global definition and diagnostic approach of laryngopharyngeal reflux (LPR) to guide primary care and specialist physicians in the management of LPR. METHODS: Forty-eight international experts (otolaryngologists, gastroenterologists, surgeons, and physiologists) were included in a modified Delphi process to revise 48 statements about definition, clinical presentation, and diagnostic approaches to LPR. Three voting rounds determined a consensus statement to be acceptable when 80% of experts agreed with a rating of at least 8/10. Votes were anonymous and the analyses of voting rounds were performed by an independent statistician. RESULTS: After the third round, 79.2% of statements (N = 38/48) were approved. LPR was defined as a disease of the upper aerodigestive tract resulting from the direct and/or indirect effects of gastroduodenal content reflux, inducing morphological and/or neurological changes in the upper aerodigestive tract. LPR is associated with recognized non-specific laryngeal and extra-laryngeal symptoms and signs that can be evaluated with validated patient-reported outcome questionnaires and clinical instruments. The hypopharyngeal-esophageal multichannel intraluminal impedance-pH testing can suggest the diagnosis of LPR when there is >1 acid, weakly acid or nonacid hypopharyngeal reflux event in 24 h. CONCLUSION: A global consensus definition for LPR is presented to improve detection and diagnosis of the disease for otolaryngologists, pulmonologists, gastroenterologists, surgeons, and primary care practitioners. The approved statements are offered to improve collaborative research by adopting common and validated diagnostic approaches to LPR. LEVEL OF EVIDENCE: 5 Laryngoscope, 134:1614-1624, 2024.

Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5-Year Update.

The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.

Multi-institutional search for patient factors associated with adverse events following tracheotomy.

BACKGROUND: Tracheotomy is a common procedure for otolaryngologists. The risk of complications is difficult to predict. This study aims to identify measurable preoperative indicators associated with adverse events following tracheotomy. METHODS: The charts of adults undergoing tracheotomy for respiratory failure at one of four university-affiliated hospitals between 1/2012 and 8/2018 were reviewed. Complications were analyzed in the context of demographics, physiologic parameters, and comorbidities. RESULTS: Among 507 tracheotomies performed, the most common complications included infection, bleeding, and cardiac arrest. Mortality was 39 % in patients with pulmonary hypertension, 42 % in those with ejection fraction ≤ 40 and 32 % in those with abnormal right ventricular function, double the rates in patients without each of these findings. CONCLUSION: Many critically ill tracheotomy patients experience significant rates of adverse events. Risk factors for mortality include ejection fraction ≤ 40, pulmonary hypertension, and abnormal ventricular function. These should be considered for use in preoperative counseling.

Correlation of Esophageal Mean Nocturnal Baseline Impedance With Markers of Laryngopharyngeal Reflux.

OBJECTIVES: Mean nocturnal baseline impedance (MNBI) is a measure of the esophageal epithelial barrier function calculated via high-resolution impedance manometry and can be used as a diagnostic tool and treatment response predictor for gastroesophageal reflux disease (GERD). However, its utility for laryngopharyngeal reflux (LPR) has been minimally studied. We aimed to investigate the relationship of MNBI between patients with suspected LPR, healthy controls, and their 24-h multichannel intraluminal impedance-pH (MII-pH) study results. METHODS: Retrospective patient series analysis was performed of patients with suspected LPR and healthy controls who underwent 24-h MII-pH monitoring. MNBI values were calculated from impedance channels at the level of the hypopharynx, proximal esophagus, and distal esophagus. We compared these MNBI values between the subject groups with secondary analysis on MII-pH results, reflux symptom index, reflux findings score, DeMeester score, and salivary pepsin levels. RESULTS: Twenty-three patients with suspected LPR and 14 healthy controls were enrolled. Decreased distal esophageal MNBI was found to be significantly decreased in patients with suspected LPR compared with healthy controls (p < 0.01) and in subjects with positive MII-pH studies compared to negative MII-pH studies (p < 0.01). There were no significant correlations of MNBI at the hypopharynx or proximal esophagus. CONCLUSION: Distal esophageal MNBI has significant correlations with many phenotypic and biological markers of LPR. These findings indicate that MNBI has the potential to be applied to LPR, similar to its emerging use as a diagnostic tool and treatment response predictor for GERD. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1927-1932, 2023.

Best Practices in Treatment of Laryngopharyngeal Reflux Disease: A Multidisciplinary Modified Delphi Study.

BACKGROUND: Laryngopharyngeal reflux (LPR) is a common otolaryngologic diagnosis. Treatment of presumed LPR remains challenging, and limited frameworks exist to guide treatment. METHODS: Using RAND/University of California, Los Angeles (UCLA) Appropriateness Methods, a modified Delphi approach identified consensus statements to guide LPR treatment. Experts independently and blindly scored proposed statements on importance, scientific acceptability, usability, and feasibility in a four-round iterative process. Accepted measures reached scores with ≥ 80% agreement in the 7-9 range (on a 9-point Likert scale) across all four categories. RESULTS: Fifteen experts rated 36 proposed initial statements. In round one, 10 (27.8%) statements were rated as valid. In round two, 8 statements were modified based on panel suggestions, and experts subsequently rated 5 of these statements as valid. Round three's discussion refined statements not yet accepted, and in round four, additional voting identified 2 additional statements as valid. In total, 17 (47.2%) best practice statements reached consensus, touching on topics as varied as role of empiric treatment, medication use, lifestyle modifications, and indications for laryngoscopy. CONCLUSION: Using a well-tested methodology, best practice statements in the treatment of LPR were identified. The statements serve to guide physicians on LPR treatment considerations.

Demographic differences in the treatment of unilateral vocal fold paralysis.

Objective: To determine the impact of patient demographics and social determinants of health on treatment pathways for unilateral vocal fold paralysis (UVFP) at a tertiary laryngology clinic. Study design: Retrospective medical record review. Methods: Patient demographics (age, gender, race, ethnicity, and insurance status) were extracted for adults diagnosed with UVFP between 2009 and 2019. Odds ratios for the associations between sociodemographic factors and UVFP treatment pathways were determined by chi-square analyses. Results: A total of 1490 UVFP diagnoses were identified during the study period with the majority being female (58%), White (85%), non-Hispanic (97%), and publicly insured (54%). Five treatment pathways were identified: observation, injection laryngoplasty, voice therapy, laryngeal framework surgery/thyroplasty, and reinnervation surgery. There were 538 patients who underwent observation, 512 injection laryngoplasty, 366 voice therapy, 136 thyroplasty, and 26 laryngeal reinnervation surgery. Males were more likely to undergo injection laryngoplasty than females (OR 1.32; CI 1.08-1.61), whereas females were more likely to undergo voice therapy (OR 1.39; CI 1.09-1.76). Patients with public insurance (OR 1.48; CI 1.03-2.14) and Hispanics (OR 2.60; CI 1.18-5.72) were more likely to undergo thyroplasty. Patients who underwent reinnervation surgery were younger than those in other treatment pathways (median: 39.1 years vs. 50.7-56.1 years). Conclusions: Gender, ethnicity, and insurance status were significantly associated with specific UVFP treatment pathways. Patients with public insurance were more likely to undergo surgical intervention than voice therapy. This data overall supports differences in care pathway utilization for UVFP based on social determinants of health. Level of evidence: Level IV.

Analysis of socioeconomic factors in laryngology clinic utilization for treatment of dysphonia.

OBJECTIVE: To evaluate the association between patient socioeconomic and demographic factors and tertiary care utilization for dysphonia in a localized metropolitan area of the American Midwest. METHODS: Multivariate regression analysis was used to correlate patient demographics and population level data (e.g., age, gender, race, insurance, median income, education level) with tertiary laryngology utilization for dysphonia care at our institution between 2000 and 2019. Initial analyses characterized tertiary laryngology utilization rates for all regional ZIP codes and correlated these data with census information for household income and education. Dysphonia patient demographics were compared among populations cared for in our entire academic Otolaryngology department, our health system, and the regional population. RESULTS: Among 1,365,021 patients in our health system, there were 7066 tertiary laryngology visits with a diagnosis of dysphonia. Dysphonia patients as compared to the overall health system were older (62.0 vs. 50.8 years), more likely to be female (63.7 vs. 50.2%) and more likely to have insurance (98.4 vs. 87.5%, all p < .001). Patient and population-level factors including insurance status, education, and black race showed positive correlation with laryngology utilization while median income did not. CONCLUSIONS AND RELEVANCE: Insurance status, education level, and race correlated with utilization of tertiary laryngology services for the evaluation of dysphonia in our community, while median income did not. Black patients utilized tertiary laryngology care at higher rates compared to departmental and regional population utilization data. These results underscore important demographic and disease-specific factors that may affect utilization of subspecialty care in Otolaryngology. LEVEL OF EVIDENCE: IV.

Twenty-One for 2021: The Most Influential Papers in Laryngology Since 2000.

OBJECTIVES/HYPOTHESIS: To identify the most influential publications in laryngology since 2000. STUDY DESIGN: Modified Delphi process. METHODS: Samples of laryngologists drawn from editors of leading journals, organization officers, and thought leaders were invited to participate in a modified Delphi identification of influential laryngology papers. Influential was defined as follows: yielding meaningful practice changes, catalyzing further work as a foundation for an important topic, altering traditional views, or demonstrating durability over time. Quality and validity were not among the selection criteria. Each participant nominated 5 to 10 papers in Round 1. These nominations, augmented with papers from bibliometric analysis, were narrowed further in Round 2 as participants identified their top 20. The 40 papers with the most Round 2 votes were discussed by video conference and then subjected to Round 3 voting, with each participant again selecting their top 20 most influential papers. Final results were collated by the number of Round 3 votes. RESULTS: Sixteen of 18 invited laryngologists participated overall (all 16 in Rounds 1 and 3; 14 in Round 2). Twenty-one papers were identified as most influential. One paper appeared on all 16 Round 3 lists; three papers with eight (50%) votes each were lasted to make the list. Eleven of these 21 focused on voice; three each related to cancer, airway, and swallowing; and one encompassed all of these clinical areas. CONCLUSIONS: This list of 21 influential laryngology papers serves to focus further research, provides perspective on recent advances within the field, and is an educational resource for trainees and practicing physicians. LEVEL OF EVIDENCE: NA Laryngoscope, 132:406-412, 2022.

Normative Ambulatory Reflux Monitoring Metrics for Laryngopharyngeal Reflux: A Systematic Review of 720 Healthy Individuals.

OBJECTIVES: To review the normative data for acid, weakly acid, and nonacid proximal esophageal (PRE) and hypopharyngeal reflux (HRE) events in diagnosing laryngopharyngeal reflux (LPR) using ambulatory reflux monitoring. DATA SOURCES: PubMed, Cochrane Library, and Scopus. REVIEW METHODS: A literature search was conducted about the normative data for PRE and HRE on multichannel intraluminal impedance-pH monitoring (MII-pH), hypopharyngeal-esophageal MII-pH (HEMII-pH), or oropharyngeal pH monitoring using PICOTS (population, intervention, comparison, outcome, timing, and setting) and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statements. Outcomes reviewed included device characteristics, impedance/pH sensor placements, study duration, number/average and percentiles of PRE or HRE occurrence, and the event characteristics (pH, composition, and position). RESULTS: Of 154 identified studies, 18 met criteria for analysis, including 720 healthy individuals. HEMII-pH, MII-pH, and oropharyngeal pH monitoring were used in 7, 6, and 5 studies, respectively. The definition and inclusion/exclusion criteria of healthy individuals varied substantially across studies, with 6 studies considering only digestive symptoms to exclude potential LPR patients. Substantial heterogeneity across studies was noted, including impedance/pH sensor placements/configurations and definitions of composition (liquid, gas, mixed) and type (acid, weakly acid, nonacid) of PRE/HRE. The 95th percentile thresholds were 10 to 73 events for PRE, 0 to 10 events for HRE on HEMII-pH, and 40 to 128 for events with pH <6.0 on oropharyngeal pH monitoring. Most HREs were nonacid and occurred upright. The mean HRE among healthy individuals was 1. CONCLUSION: The low number of studies and the heterogeneity in inclusion criteria, definitions, and characterization of PRE and HRE limit the establishment of consensual normative criteria for LPR on ambulatory reflux monitoring. Future large multicenter studies are needed.

Impact of subspecialty training on management of laryngopharyngeal reflux: results of a worldwide survey.

OBJECTIVE: To study the management of laryngopharyngeal reflux (LPR) among the subspecialties of practicing otolaryngology-head and neck surgeons and their trainees. METHODS: A survey was sent to over 8000 otolaryngologists (OTOHNS) over 65 countries, utilizing membership lists of participating otolaryngological societies. The outcomes were answers to questions regarding LPR knowledge and practice patterns, and included queries about its definition, prevalence, clinical presentation, diagnosis, and treatment. RESULTS: Of the 824 respondents, 658 practiced in one specific otolaryngologic subspecialty. The symptoms and findings thought to be the most related to LPR varied significantly between subspecialists. Extra-laryngeal findings were considered less by laryngologists while more experienced OTOHNS did not often consider digestive complaints. Compared with colleagues, otologists, rhinologists and laryngologists were less aware of the involvement of LPR in otological, rhinological and laryngological disorders, respectively. Irrespective of subspecialty, OTOHNS consider symptoms and signs and a positive response to empirical therapeutic trial to establish a LPR diagnosis. Awareness regarding the usefulness of impedance pH-studies is low in all groups. The therapeutic approach significantly varies between groups, although all were in agreement for the treatment duration. The management of non-responder patients demonstrated significant differences among laryngologists who performed additional examinations. The majority of participants (37.1%) admitted to being less than knowledgeable about LPR management. CONCLUSIONS: LPR knowledge and management vary significantly across otolaryngology subspecialties. International guidelines on LPR management appear necessary to improve knowledge and management of LPR across all subspecialties of otolaryngology.

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

OBJECTIVES: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients. METHODS: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence. RESULTS: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression. CONCLUSIONS: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.

Systemic Bevacizumab for Treatment of Respiratory Papillomatosis: International Consensus Statement.

OBJECTIVES/HYPOTHESIS: The purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality. STUDY DESIGN: Delphi method-based survey series. METHODS: A multidisciplinary, multi-institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work-up. RESULTS: The international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18). CONCLUSION: This consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best-practice applications of systemic bevacizumab for patients with early-onset or less-severe disease phenotypes. LEVEL OF EVIDENCE: 5 Laryngoscope, 131:E1941-E1949, 2021.

RNA Sequencing Reveals Cancer-Associated Changes in Laryngeal Cells Exposed to Non-Acid Pepsin.

OBJECTIVE: Laryngopharyngeal reflux (LPR) is a common affliction that contributes to laryngeal inflammation, symptoms that impact quality of life, and life-threatening illnesses such as cancer. Effective treatment strategies for LPR are lacking. Pepsin is a proinflammatory and carcinogenic element of refluxate. Investigation of molecular pathways involved in pepsin-mediated damage may lead to identification of novel biomarkers and therapeutic targets for LPR. In this study, RNA sequencing was used to examine changes in human laryngeal epithelial cells following brief pepsin insult. Cells were immortalized to generate a model to aid future study of laryngeal injury and therapeutics. STUDY DESIGN: In vitro translational. METHODS: Laryngeal epithelial cells were cultured from a patient without signs or symptoms of LPR or laryngeal cancer. Cells were treated with 0.1 mg/ml pepsin for 1 hour or normal growth media (control) prior to RNA sequencing. Cells were immortalized via HPV E6/7 and characterized by microscopy, immunohistochemistry, G-banding, and soft agar assay. RESULTS: Three hundred ninety-seven genes exhibited differences in expression with pepsin treatment (P < .05). Pathway analysis revealed association with cancer and related signaling processes including dysregulation of cancer-associated molecules, Metastasis-Associated Lung Adenocarcinoma Transcript 1 and KRT82, and the long-noncoding RNA, lipoprotein receptor-related protein 1 (LRP1)-AS, which regulates the putative pepsin receptor LRP1. CONCLUSIONS: A single, brief exposure to pepsin activated cancer-associated signaling pathways in laryngeal cells in vitro, revealing novel mechanisms by which chronic reflux may contribute to carcinogenesis. The cell line developed herein represents a novel tool in which to investigate pepsin-dysregulated pathways identified by RNA sequencing and disparities of tumor proneness of laryngeal subsites. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:121-129, 2021.

H+/K+ATPase Expression in the Larynx of Laryngopharyngeal Reflux and Laryngeal Cancer Patients.

OBJECTIVES: The gastric H+/K+ ATPase proton pump has previously been shown to be expressed in the human larynx, however its contribution to laryngopharyngeal reflux (LPR) signs, symptoms and associated diseases such as laryngeal cancer is unknown. Proton pump expression in the larynx of patients with LPR and laryngeal cancer was investigated herein. A human hypopharyngeal cell line expressing the proton pump was generated to investigate its effects. STUDY DESIGN: In-vitro translational. METHODS: Laryngeal biopsies were obtained from three LPR and eight LSCC patients. ATP4A, ATP4B and HRPT1 were assayed via qPCR. Human hypopharyngeal FaDu cell lines stably expressing proton pump were created using lentiviral transduction and examined via transmission electron microscopy and qPCR for genes associated with inflammation or laryngeal cancer. RESULTS: Expression of ATP4A and ATP4B was detected in 3/3 LPR, 4/8 LSCC-tumor and 3/8 LSCC-adjacent specimens. Expression of ATP4A and ATP4B in FaDu elicited mitochondrial damage and expression of IL1B, PTGS2, and TNFA (P < .0001); expression of ATP4B alone did not. CONCLUSIONS: Gastric proton pump subunits are expressed in the larynx of LPR and LSCC patients. Mitochondrial damage and changes in gene expression observed in cells expressing the full proton pump, absent in those expressing a single subunit, suggest that acid secretion by functional proton pumps expressed in upper airway mucosa may elicit local cell and molecular changes associated with inflammation and cancer. LEVEL OF EVIDENCE: NA Laryngoscope, 131:130-135, 2021.

Involvement of Laryngopharyngeal Reflux in Select Nonfunctional Laryngeal Diseases: A Systematic Review.

OBJECTIVES: To investigate the existing published evidence supporting the role of laryngopharyngeal reflux (LPR) in the development of the select nonfunctional laryngeal diseases of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. DATA SOURCES: PubMed, Cochrane Library, and Scopus. REVIEW METHODS: A systematic review was performed by 3 independent investigators for studies providing information about the prevalence and role of LPR in the development of laryngotracheal stenosis, granuloma, leukoplakia, and laryngeal infections. Diagnostic criteria and clinical outcome evaluation of included studies were analyzed with PRISMA criteria. RESULTS: Of the 64 relevant publications, 27 clinical and 4 basic science studies were included. Ten studies used objective reliable examinations for LPR diagnosis (eg, dual- or triple-probe or oropharyngeal pH monitoring, multichannel intraluminal impedance-pH monitoring, or pepsin detection). According to the bias analysis and the results of studies, the association between LPR and laryngotracheal stenosis, leukoplakia, laryngeal papillomatosis, or vocal fold granuloma remains poorly demonstrated. There is a notable heterogeneity among included studies regarding their inclusion criteria, diagnostic methods, and clinical outcome evaluation. Although some experimental findings support the involvement of bile salts and other gastroduodenal proteins active in alkaline pH, no included clinical studies assessed the role of nonacid and mixed reflux through multichannel intraluminal impedance-pH monitoring. CONCLUSION: The involvement of LPR in the development of leukoplakia, laryngotracheal stenosis, vocal fold granuloma, and laryngeal papillomatosis is currently not demonstrated. The potential relationship between LPR and these select nonfunctional laryngeal diseases must be confirmed through future clinical and experimental studies considering acid, nonacid, and mixed LPR.

Management of Laryngopharyngeal Reflux Around the World: An International Study.

OBJECTIVE: To investigate worldwide practices of otolaryngologists in the management of laryngopharyngeal reflux (LPR). METHODS: An online survey was sent on the management of LPR to members of many otolaryngological societies. The following aspects were evaluated: LPR definition, prevalence, clinical presentation, diagnosis, and treatment. RESULTS: A total of 824 otolaryngologists participated, spread over 65 countries. The symptoms most usually attributed to LPR are cough after lying down/meal, throat clearing and globus sensation while LPR-related findings are arytenoid erythema and posterior commissure hypertrophy. Irrespective to geography, otolaryngologists indicate lack of familiarity with impedance pH monitoring, which they attribute to lack of knowledge in result interpretation. The most common therapeutic regimens significantly vary between world regions, with a higher use of H2 blocker in North America and a lower use of alginate in South America. The duration of treatment also significantly varies between different regions, with West Asia/Africa and East Asia/Oceania otolaryngologists prescribing medication for a shorter period than the others. Only 21.1% of respondents are aware about the existence of nonacid LPR. Overall, only 43.2% of otolaryngologists believe themselves sufficiently knowledgeable about LPR. CONCLUSIONS: LPR knowledge and management significantly vary across the world. International guidelines on LPR definition, diagnosis, and treatment are needed to improve knowledge and management around the world. LEVEL OF EVIDENCE: N.A. Laryngoscope, 131:E1589-E1597, 2021.