Characteristics of adults with potential refractory chronic cough identified using an algorithm designed for administrative claims databases: A descriptive study.

Objective As population-based studies describing the characteristics of patients with refractory chronic cough (RCC) are sparse, the objective of this descriptive study was to identify and describe such patients using an algorithm developed for administrative claims databases and requiring validation in future. Methods We identified adults with chronic cough (N = 782,121) from Optum Clinformatics™ Data Mart as individuals with a 'cough event' (primary cough event; based on ICD codes/relevant prescriptions) and ≥2 cough events in the 56-180 preceding days. We applied several exclusion criteria to identify potential RCC cases and stratified them into probable, possible, and unlikely RCC cohorts by the number of cough events during 1-year follow up (≥3, 1-2 or 0 events, respectively). Patient characteristics were described during the year before the primary cough event and follow up. Results 16.8% (n = 131,772) of patients with chronic cough were potential RCC cases: 25.8% probable, 35.9% possible and 38.3% unlikely. The majority were female (66.4-70.5%); median age was 53-60 years. The most common comorbidities and cough-associated complications at baseline were: allergic rhinitis (30.7-39.1%), hypertension (37.3-47.7%), gastro-oesophageal reflux disease (23.7-34.3%), asthma (18.1-27.3%), insomnia (6.3-8.3%) and stress incontinence (2.5-3.9%). Among probable RCC cases, use of several medications was higher during follow up versus baseline: 52.7% versus 49.0% (cough treatments), 73.3% versus 69.0% (respiratory drugs), 40.5% versus 34.2% (gastrointestinal drugs) and 58.8% versus 56.1% (psychotherapeutics). Conclusion Our algorithm requires validation but provides a starting point to identify patients with RCC in claims databases in future studies.

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.

Depression and anxiety in patients with head and neck cancer undergoing free flap reconstruction.

PURPOSE: To determine the prevalence and severity of depression and anxiety in patients with head and neck cancer (HNC) undergoing treatment with free-flap (FF) reconstruction. METHODS: Participants with HNC undergoing FF reconstruction were given the validated 9-item Patient Health Questionnaire (PHQ-9) and a 7-item Generalized Anxiety Disorder (GAD-7) questionnaire prior to surgery. Patient factors and responses were analyzed. RESULTS: Seventy-one patients were included. Mean (SD) pre-operative PHQ-9 was 7.6 (7.04) with 34 % (n = 24) having moderate to severe depression. Mean (SD) pre-operative GAD-7 was 6.5 (6.86) with 30 % (n = 21) having moderate to severe anxiety. CONCLUSION: Prevalence of depression and anxiety is high in this cohort and undiagnosed in 22 % and 18 % of patients, respectively. Due to the findings, it is prudent to screen HNC patients at initial diagnosis and offer mental health services.

Interdisciplinary collaboration in the diagnosis and management of chronic cough: the role and importance of primary care providers.

Chronic cough (CC) is associated with many conditions, so identifying contributing causes poses a diagnostic challenge. However, guidelines written for US physicians do not explicitly outline suggested roles for primary care providers (PCPs) in the approach to patients with CC, including refractory or unexplained CC. The objective of this review is to describe the role of PCPs in the diagnosis and treatment of CC in adults. This narrative review draws upon literature (identified via a PubMed search performed January 9, 2023, using primary care/disease state-related terms) and expertise from specialist physicians to provide recommendations for CC management in primary care. Cough is one of the top reasons patients seek care from PCPs; accordingly, PCPs are often the first physicians to conduct workup and initiate treatment. Patients with CC often experience a burdensome cough that lasts for years, have high healthcare resource utilization (HCRU), undergo multiple or failed treatment trials, and have limited success finding an etiology. Although specialist referral may be needed for many diagnostic tests, initial aspects of CC workup and management should be completed in primary care. Often more accessible than specialists, real-world evidence on HCRU suggests PCPs are important stakeholders in diagnosing and managing CC, including during initial workup and treatment for the most common causes of CC (i.e. upper-airway cough syndrome, asthma, noneosinophilic asthmatic bronchitis, and gastroesophageal reflux disease). Thorough workup at the primary care level may facilitate earlier identification of CC cause(s), improving patient journey to diagnosis and management.

Importance of PET/CT in Initial Workup of Head and Neck Squamous Cell Carcinoma.

Objective: Assess the impact of positron emission tomography/computed tomography (PET/CT) on disease staging at presentation in patients with head and neck squamous cell carcinoma. Study Design: Retrospective cross-sectional review. Setting: Academic multicenter single institution (Geisinger Health System). Methods: All patients who had PET/CT imaging during workup for head and neck squamous cell carcinoma were included in the study. Pre- and post-PET/CT clinical staging were recorded. Statistical analyses were performed for patients with a change in clinical staging or detection of second primary malignancies on PET/CT. Results: A total of 292 patients were included in the study, 238 of whom underwent PET/CT imaging as part of their initial workup. Twenty-eight (11.9%) patients were clinically upstaged on PET/CT with 7 patients having treatment alterations based on imaging. Eighteen (7.6%) patients were found to have second primary malignancies on PET/CT. Conclusion: The current study further illustrates the importance of PET/CT in the workup of head and neck squamous cell carcinoma. Without the inclusion of PET/CT imaging, 19.3% of patients would have either been staged inappropriately or had second primary malignancies missed, again confirming the necessity of comprehensive functional imaging during the initial pretreatment workup.

Cancer Risk in Barrett's Esophagus: A Clinical Review.

Esophageal adenocarcinoma (EAC) is rapidly increasing in incidence and is associated with a poor prognosis. Barrett's esophagus (BE) is a known precursor of esophageal adenocarcinoma. This review aims to explore Barrett's esophagus, esophageal adenocarcinoma, and the progression from the former to the latter. An overview of the definition, diagnosis, epidemiology, and risk factors for both entities are presented, with special attention being given to the areas of debate in the literature. The progression from Barrett's esophagus to esophageal adenocarcinoma is reviewed and the relevant molecular pathways are discussed. The definition of Barrett's esophagus remains debated and without international consensus. This, alongside other factors, has made establishing the true prevalence of Barrett's esophagus challenging. The degree of dysplasia can be a histological challenge, but is necessary to guide clinical management. The progression of BE to EAC is likely driven by inflammatory pathways, pepsin exposure, upregulation of growth factor pathways, and mitochondrial changes. Surveillance is maintained through serial endoscopic evaluation, with shorter intervals recommended for high-risk features.

Pepsinogen/Proton Pump Co-Expression in Barrett's Esophageal Cells Induces Cancer-Associated Changes.

EDUCATIONAL OBJECTIVE: At the conclusion of this presentation, participants should better understand the carcinogenic potential of pepsin and proton pump expression in Barrett's esophagus. OBJECTIVE: Barrett's esophagus (BE) is a well-known risk factor for esophageal adenocarcinoma (EAC). Gastric H+ /K+ ATPase proton pump and pepsin expression has been demonstrated in some cases of BE; however, the contribution of local pepsin and proton pump expression to carcinogenesis is unknown. In this study, RNA sequencing was used to examine global transcriptomic changes in a BE cell line ectopically expressing pepsinogen and/or gastric H+ /K+ ATPase proton pumps. STUDY DESIGN: In vitro translational. METHODS: BAR-T, a human BE cell line devoid of expression of pepsinogen or proton pumps, was transduced by lentivirus-encoding pepsinogen (PGA5) and/or gastric proton pump subunits (ATP4A, ATP4B). Changes relative to the parental line were assessed by RNA sequencing. RESULTS: Top canonical pathways associated with protein-coding genes differentially expressed in pepsinogen and/or proton pump expressing BAR-T cells included those involved in the tumor microenvironment and epithelial-mesenchymal transition. Top upstream regulators of coding transcripts included TGFB1 and ERBB2, which are associated with the pathogenesis and prognosis of BE and EAC. Top upstream regulators of noncoding transcripts included p300-CBP, I-BET-151, and CD93, which have previously described associations with EAC or carcinogenesis. The top associated disease of both coding and noncoding transcripts was cancer. CONCLUSIONS: These data support the carcinogenic potential of pepsin and proton pump expression in BE and reveal molecular pathways affected by their expression. Further study is warranted to investigate the role of these pathways in carcinogenesis associated with BE. LEVEL OF EVIDENCE: NA Laryngoscope, 133:59-69, 2023.

Incidence and Prevalence of Cough in a Rural Health System: A 20-Year Study.

OBJECTIVE: Understanding the cough population is critical to addressing clinical needs and gaps in best practice. We sought to characterize and stratify cough patients with the hypothesis that there are opportunities to improve access to care in our health system and characterize the population. METHODS: Following institutional review board exempt status, a retrospective electronic record review was performed on all patients coded with ICD-9 786.2 or ICD-10 is R05 from January 1, 2001 through December 31, 2020 at our health system. Inclusion criteria were one or more visits for cough. The subgroup with more than one visit in each of 2 years was classified as multiple encounters. Patients were characterized by sex, age at first cough encounter, number of cough encounters, smoking status, and insurance status. Results were stratified by year, calculating frequencies, and percentages. RESULTS: There were 302,284 unique patients diagnosed with cough, among 1,764,387 patients seen in our health system, representing an average incidence of 3.0% (2.7%-3.7%) and prevalence of 4.9% (3.1%-5.6%). New single encounter cough patients totaled 179,963, and new multiple encounter cough patients totaled 122,321. Of the 39,828,073 total encounters, there were 469,802 for new or existing cough (1.17%-1.73% annually). The age at initial presentation demonstrated 36.5% seen <10 years old, with an even distribution over the remaining decades of life. The majority were seen for cough once, but 23.8% of group two patients had two or more visits for cough in a year. CONCLUSION: We demonstrate a lower-than-expected incidence and prevalence of cough in our health population, suggesting challenges with access to care when compared to 10% prevalence and 3% of encounters previously documented in the literature. The study also provides a platform to explore the importance of pediatric cough, as well as population health and the longitudinal journey of cough patients in underserved areas. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1191-1196, 2023.

Tracheotomy Timing and Outcomes in the Critically Ill: Complexity and Opportunities for Progress.

OBJECTIVES/HYPOTHESIS: To characterize the effects of tracheotomy timing at our institution on intensive care unit (ICU) length of stay (LOS) and overall hospital LOS. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective study was performed at a tertiary care medical center for patients undergoing tracheotomy over 2.5 years from January 1, 2016 through June 30, 2018. Demographics, survival, duration of endotracheal intubation, timing of tracheotomy, and ICU and overall hospital LOS were assessed. Tracheotomy was considered early (ET) if it was performed by day 7 of mechanical ventilation and late (LT) thereafter. Readmission, mortality, and costs were also tabulated for each aggregate group. Nonparametric statistics were used to compare results. RESULTS: Of the 536 patients included in the analysis, 160 received tracheotomy early and 376 late. Differences between age and sex were not statistically significant. Duration of total ICU stay was shortened by 65% (12.84 ± 17.69 days vs. 38.49 ± 26.61 days; P < .0001), and length of overall hospital course was reduced by 54% (22.71 ± 26.65 days vs. 50.37 ± 34.20 days; P < .0001) in the early tracheotomy group. Observed/expected (O/E) values standardized results to case mix index and revealed LOS of 1.5 for ET and 2.5 for LT, and mortality of 0.76 for ET and 1.25 for LT, and comparable readmissions of both groups. CONCLUSIONS: Early tracheotomy in ICU patients is associated with earlier ICU discharge, decreased length of overall hospital stay, and lower mortality when controlling for case mix index. Opportunities exist to optimize patient outcomes and O/E performance. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:282-287, 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.

Biomarkers for Malignant Potential in Vocal Fold Leukoplakia: A State of the Art Review.

OBJECTIVE: To explore biomarkers that are candidates for understanding potential degeneration to malignancy of vocal fold leukoplakia (VFL), with the goal of guiding future diagnostic and treatment recommendations. DATA SOURCES: PubMed and Medline search engines. REVIEW METHODS: A systematic review was conducted by searching the following key words: vocal fold or laryngeal, coupled with leukoplakia or dysplasia, and combined with the term prognostic markers. We collated the biomarkers and their significance, followed by observing the power of their evidence by assessing the quality of the studies according to guidelines of tumor marker prognostic studies (REMARK). CONCLUSIONS: Prognostic biomarkers in the 16 studies are generally divided into 3 categories according to their biological roles: proliferation (Ki-67, CK-1 RS14024 SNP), cell cycle control (P53, p16, cyclin D1, p57kip2, interleukin-10 [IL-10], miR-10a, and miR-34c), cell adhesion, and invasion (neutrophil-to-lymphocyte ratio, OPN/CD44v6 axis, MMP-1, vascular endothelial growth factor A, MMP-9, serpin peptidase inhibitor 1, plasminogen activator, CTNN/B1, ß-catenin, NANOG, HERG1). The prognostic use of these biomarkers is limited due to the variable methodologies, study design, assay methods, and statistical analysis performed. IMPLICATIONS FOR PRACTICE: Prognostic factors in vocal fold leukoplakia have important clinical implications regarding the potential for malignant degeneration. Although further study is needed, the currently available evidence suggests that p53, p16, cyclin D1, IL-10, NLR, OPN and CD44v6, CTNNB1, and CTTN and FAK might be of particular interest in determining prognosis of VFL as related to malignancy. Future, large, well-designed, prospective studies are expected to determine the prognostic power of these biomarkers before their implementation in routine clinical practice.

Laryngeal Leukoplakia: State of the Art Review.

OBJECTIVE: This state-of-the-art article reviews the epidemiology, diagnosis, and management of vocal fold leukoplakia, with focus on recent advances. It focuses on the clinical challenges that otolaryngologists face balancing both oncological efficacy and functional outcomes in leukoplakia and presents the current philosophies and techniques to consider when managing such patients. DATA SOURCES: PubMed/MEDLINE. REVIEW METHODS: We conducted a detailed review of publications related to vocal cord and laryngeal leukoplakia, dysplasia, hyperkeratosis, leukoplakia endoscopy, and leukoplakia management focusing specifically on oncologic outcomes, voice preservation, current and emerging diagnosis, and management techniques. CONCLUSIONS: There has been a paradigm shift away from performing "vocal cord stripping" procedures that can cause irreversible hoarseness toward voice preservation surgery while achieving comparable oncologic control. Surgical technical and instrumental developments have been designed to maximally treat superficial disease while preserving underling vibratory mucosa. Recent improvements in histopathological grading systems and advances in biomarker classification may allow for improved oncologic risk stratification. Furthermore, improvements in endoscopic imaging capabilities and contact endoscopy are currently being studied for their potential diagnostic significance. IMPLICATIONS FOR PRACTICE: To optimally manage vocal fold leukoplakia, the otolaryngologist should become familiar with the oncologic implications of the disease and the importance of obtaining pathologic diagnosis to rule out malignancy. In addition, the surgeon should maintain surgical techniques and knowledge of available instruments and lasers that can assist in surgical management while prioritizing the preservation of vibratory tissue and voice quality. Finally, the surgeon and the patient should understand the clinical importance of routine endoscopic surveillance.

Relationship between Dysarthria and Oral-Oropharyngeal Dysphagia: The present evidence.

There is a high prevalence of dysphagia in patients with neuromuscular diseases and stroke, and consequences can be profound. However, the correlation of dysarthria and oral-oropharyngeal dysphagia remains unclear. This review aimed to define the clinical co-presentation of dysarthria and dysphagia in this population. A PubMed search to identify literature on the prevalence of dysarthria and dysphagia was systematically conducted in the English language literature since 1995. Subjective and objective outcomes instruments were identified for both dysarthria and dysphagia. Studies that included prevalence and co-presentation were included. Inclusion and exclusion criteria were applied according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). Of the 1,056 articles identified in the search, 20 articles met the search criteria. An additional 4 articles were examined for a total of 24 articles for analysis. Dysarthria and dysphagia were found to be highly prevalent among patients with neuromuscular disease (NMD). Overall, there was a higher prevalence of dysarthria than dysphagia. Of those patients with dysphagia, some reports estimate 76-90% of patients with NMD also had dysarthria. Dysarthria is a strong clinical clue to the presence of dysphagia. Existing subjective questionnaires may not reveal the presence of oropharyngeal dysphagia, but objective measures are more revealing. Further study to correlate the degree of dysarthria and severity of oral-oropharyngeal dysphagia are warranted.

Esophageal pepsin and proton pump synthesis in barrett's esophagus and esophageal adenocarcinoma.

OBJECTIVES/HYPOTHESIS: Gastroesophageal reflux disease and associated metaplasia of the esophagus (Barrett's esophagus [BE]) are primary risk factors for esophageal adenocarcinoma (EAC). Widespread use of acid suppression medications has failed to stem the rise of EAC, suggesting that nonacid reflux may underlie its pathophysiology. Pepsin is a tumor promoter in the larynx and has been implicated in esophageal carcinogenesis. Herein, specimens from the esophageal cancer spectrum were tested for pepsin presence. Pepsin-induced carcinogenic changes were assayed in an esophageal cell culture model. STUDY DESIGN: Laboratory analysis. METHODS: Pepsin was assayed in reflux and cancer free esophagi, BE, EAC, and esophageal cancer lacking association with reflux (squamous cell carcinoma [SCC]). Refluxed or locally synthesized pepsin was assayed by Western blot. Local synthesis of pepsin and proton pumps was assayed via reverse transcription-polymerase chain reaction. The effect of pepsin on BE and EAC markers was investigated via enzyme-linked immunosorbent assay and quantitative polymerase chain reaction in human esophageal epithelial cells treated with pepsin or control diluent. RESULTS: Pepsinogen and proton pump mRNA were observed in BE (3/5) and EAC (4/4) samples, but not in normal adjacent specimens, SCC (0/2), or reflux and cancer-free esophagi. Chronic pepsin treatment (0.1-1 mg/mL, 4 weeks) of human esophageal cells in vitro induced BE and EAC markers interleukin 8 and KRT8 and depleted normal esophageal marker KRT10 (P < .05) expression. CONCLUSIONS: Local synthesis of pepsin and proton pumps in BE and EAC is not uncommon. Absence of these molecules in normal (noncancer) esophagi, SCC, and in vitro data support a role for pepsin in reflux-attributed carcinogenic changes in the esophagus. LEVEL OF EVIDENCE: NA Laryngoscope, 129:2687-2695, 2019.

Otolaryngology Aspects of Chronic Cough.

Cough is an increasingly important public health concern, and diagnosis and treatment can be challenging in these complex patients. The purpose of this review is to address the roles of otolaryngology in understanding pathophysiology, and unique aspects in their diagnosis and management. Evidence-based best practice through clinical practice guidelines for cough is emphasized. A step-wise description of the interrelated pathophysiology is used to gain a deeper understanding of contributing disease states and the importance of synergistic effects on cough. Unique perspectives exist from an otolaryngology perspective regarding chronic cough. Included here are the premier role of the larynx, immunity, and the microbiome in the Unified Airway, the interconnected nature of reflux disease with respiratory physiology, a spectrum of neurologic diseases tying aspiration to cough, and maladaptive neuro-based behaviors. Otolaryngology aspects of chronic cough encompass the composite nature of the disease with all of its contributions.

Laryngeal inflammatory response to smoke and vape in a murine model.

PURPOSE: To build a murine model for tobacco smoke and electronic cigarette vapor exposure to characterize the inflammatory and immune responses in the larynx. MATERIALS AND METHODS: In this pilot study, twenty-four wild-type C57BL/6 mice were divided into four groups: smoke, vapor with nicotine, vapor without nicotine, and air only. Following daily exposure for 4 months, larynges were dissected and processed with cytokine detection arrays. Each laryngeal cytokine level between the four different groups was analyzed statistically by using statistical analysis software (SAS) to calculate the analysis of variance (ANOVA). RESULTS: IL-4 was the only cytokine found to achieve statistically significant different levels in this study, with elevated levels of IL-4 in the tobacco smoke and vapor with nicotine groups compared to the levels found in the vapor without nicotine and air only groups (p = 0.0418). While statistically non-significant, prominent findings revealed up-regulation of TGF-ß2 and TGF-ß3 in the smoke group, but near-normal levels of TGF-ß2 and TGF-ß3 and suppression of IL-10 in the vapor groups (p > 0.05). CONCLUSION: The potential utility of the murine model is established for studying the inflammatory and immune effects of tobacco smoke and vapor on the mammalian larynx. IL-4 levels in mice larynges were significantly elevated in the tobacco smoke and vapor with nicotine groups.