How to diagnose GERC more effectively: reflections on post-reflux swallow-induced peristaltic wave index and mean nocturnal baseline impedance.

INTRODUCTION: Post-reflux swallow-induced peristaltic wave index (PSPWI) and mean nocturnal baseline impedance (MNBI) are novel parameters reflect esophageal clearance capacity and mucosal integrity. They hold potential in aiding the recognition of gastroesophageal reflux-induced chronic cough (GERC). Our study aims to investigate their diagnostic value in GERC. METHODS: This study included patients suspected GERC. General information and relevant laboratory examinations were collected, and final diagnosis were determined following guidelines for chronic cough. The parameters of multichannel intraluminal impedance-pH monitoring (MII-pH) in patients were analyzed and compared to explore their diagnostic value in GERC. RESULTS: A total of 186 patients were enrolled in this study. The diagnostic value of PSPWI for GERC was significant, with the area under the working curve (AUC) of 0.757 and a cutoff value of 39.4%, which was not statistically different from that of acid exposure time (AET) (p > 0.05). The combined diagnostic value of AET > 4.4% and PSPWI < 39.4% was superior to using AET > 4.4% alone (p < 0.05). Additionally, MNBI and distal MNBI also contributed to the diagnosis of GERC, with AUC values of 0.639 and 0.624, respectively. AET > 4.4% or PSPWI < 39.4% is associated with a 44% reduction in missed diagnoses of non-acid GERC compared to AET > 6.0% or symptom association probability (SAP) ≥ 95%, and may be more favorable for identifying GERC. CONCLUSION: The diagnostic value of PSPWI for GERC is comparable to that of AET. Combining PSPWI < 39.4% or AET > 4.4% can improve the diagnostic efficiency by reducing the risk of missed diagnoses in cases where non-acid reflux is predominant. Distal MNBI and MNBI can serve as secondary reference indices in the diagnosis of GERC.

Narrative review of relationship between chronic cough and laryngopharyngeal reflux.

Gastroesophageal reflux disease (GERD) as a possible cause of chronic cough is known for decades. However, more than 75% of patients with extraoesophageal symptoms do not suffer from typical symptoms of GERD like pyrosis and regurgitations and have negative upper gastrointestinal endoscopy. For such a condition term laryngopharyngeal reflux (LPR) was introduced and is used for more than two decades. Since the comprehensive information on relationship between chronic cough and LPR is missing the aim of this paper is to summarize current knowledge based on review of published information during last 13 years. Laryngopharyngeal reflux is found in 20% of patients with chronic cough. The main and recognized diagnostic method for LPR is 24-h multichannel intraluminal impedance-pH (MII-pH) monitoring, revealing reflux episodes irritating the upper and lower respiratory tract mucosa. The treatment of LPR should be initiated with dietary and lifestyle measures, followed by proton pump inhibitor (PPI) therapy and other measures. Despite progress, more research is needed for accurate diagnosis and targeted therapies. Key areas for exploration include biomarkers for diagnosis, the impact of non-acid reflux on symptom development, and the efficacy of new drugs. Further studies with a focused population, excluding other causes like asthma, and using new diagnostic criteria for LPR are essential. It's crucial to consider LPR as a potential cause of unexplained chronic cough and to approach diagnosis and treatment with a multidisciplinary perspective.

Identifying Practice Gaps Among Otolaryngology Providers for the Treatment of Chronic Cough.

Objective: Increasing evidence over the last decade suggests that many cases of unexplained chronic cough (UCC) have a neurogenic etiology, with laryngeal hypersensitivity (LH) being identified as a key mechanism. Official guidelines since 2015 have adopted use of neuromodulators and adjuvant speech therapy as a result, but historically implementation of guidelines is slow. Our survey aimed to investigate gaps in diagnosis and management practices of otolaryngology providers in caring for patients with UCC. Study Design: Cross-sectional study. Setting: Survey. Methods: 12-item survey was distributed to 110 otolaryngology practitioners experienced in diagnosis and treatment of chronic cough at a regional otolaryngology continuing education conference. Statistical analysis included Kendall's Tau Rank Correlation to measure the ordinal association between responses to questions, and Fisher's exact test to determine if there were associations between responses and years of career experience. Results: Forty eligible respondents underwent subsequent analysis. There was no association between frequency of identifying LH as a primary etiology and use of neuromodulators (τ = 0.23, P = .10). However, there was a significant correlation between LH and referrals to speech therapy (τ = 0.27, P = .05). Fisher's exact test did not reveal any significant differences among any responses based on practitioner experience. Conclusion: Our results indicate a possible disparity in treatment of UCC with neuromodulators and the utilization of speech therapy despite guideline recommendations advocating for neuromodulators with adjuvant speech therapy. Further research with larger sample sizes and more specific inquiries is necessary to elucidate this association and control for any regional differences.

Chronic Cough and Cerebellar Ataxia With Neuropathy and Bilateral Vestibular Areflexia Syndrome (CANVAS): Screening for Mutations in Replication Factor C Subunit 1 (RFC1).

INTRODUCTION: A common complaint in patients is chronic cough (CC), which may be refractory (RCC) or unexplained (UCC). Recent studies point, as a possible cause of CC, to the hereditary cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS), with an estimated carrier prevalence of 1 in 20000. AIM: In patients with CC, determine the prevalence of the biallelic (AAGGG)exp mutation in replication factor C subunit 1 (RFC1) responsible for CANVAS, test the usefulness of the Rydel-Seiffer fork test, and evaluate patient quality of life (QoL). METHODS: Clinical and functional data were collected for the 33 included patients undergoing CC studies in our specialized unit. Performed were an etiological study of CC following European Respiratory Society recommendations, a genetic study of RFC1 mutations, and Rydel-Seiffer fork testing to detect possible peripheral vibratory sensitivity impairment. Administered to evaluate QoL were 4 questionnaires. RESULTS: Prevalence of biallelic (AAGGG)exp in RFC1 was 6.1% (n=2) overall, increasing to 7.1% in the RCC subgroup, and to 33.3% in the Rydel-Seiffer fork altered results subgroup. Prevalence of monoallelic (AAGGG)exp in RFC1 was 18.2% (n=6) overall, rising to 50.0% (n=2) in the UCC subgroup. CONCLUSION: Genetic screening for (AAGGG)exp in RFC1, and also use of the Rydel-Seiffer fork test, should be considered in specialized CC consultations for patients with RCC and UCC. Detecting possible CANVAS symptoms in CC studies would identify candidates for early genetic screening, of interest in reducing the disease burden for patients and health systems alike.

Pharmacodynamics, pharmacokinetics and CYP3A4 interaction potential of the selective P2X3 receptor antagonist filapixant: A randomized multiple ascending-dose study in healthy young men.

AIMS: We report on investigations exploring the P2X3-receptor antagonist filapixant's effect on taste perception and cough-reflex sensitivity and describe its pharmacokinetics, including its CYP3A4-interaction potential. METHODS: In a randomized, placebo-controlled, double-blind study, 3 × 12 healthy men (18-45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste-strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. RESULTS: Taste disturbances were observed mainly in the 250-mg group: six of nine participants (67%) in this group reported hypo- or dysgeusia in the questionnaire; eight participants (89%) reported taste-related adverse events. Five participants (56%) had a decrease in overall taste-strips-test scores ≥2 points (point estimate -1.1 points, 90% confidence interval [-3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co-administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration-time curve ratios and 90% confidence intervals were within 80-125%. No serious or severe adverse events were reported. CONCLUSIONS: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor-selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough-challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential.

Chronic cough diagnosis, treatment, and referral practices among family physicians in the United States: a survey study.

BACKGROUND: Cough is one of the most common presenting problems for patients in primary care and is largely managed in primary care clinical settings. Family physicians' familiarity with chronic cough guidelines and the extent to which these guidelines translate into everyday practice have not been well described. The objective of this study was to characterize current diagnosis, treatment, and referral practices among family physicians and to identify potentially impactful strategies to optimize chronic cough management in primary care. METHODS: We conducted a cross-sectional survey of 5,000 family physicians to explore diagnosis, treatment, and referral practices related to chronic cough management in adults in primary care. Respondents completed the survey via paper or online. The outcome measures were self-reported numeric ratings and responses related to the survey elements. RESULTS: 588 surveys were completed (11.8% response rate). About half (49.6%) of respondents defined chronic cough in a manner consistent with the American College of Chest Physicians (ACCP) chronic cough guidelines, with the rest differing in opinion primarily regarding duration of symptom presentation. Respondents reported trying to rule out most common causes of chronic cough themselves before referring (mean 3.41 on a 4-point scale where 4 is "describes me completely") and indicated a desire for more resources to help them manage and treat chronic cough. Years in practice and rural/urban setting influenced diagnosis and referral practices. CONCLUSIONS: Family physicians see chronic cough as a complicated condition that can be and is often diagnosed and treated entirely in a primary care setting. They also value the ability to refer in complex cases. Our results support that family physicians provide evidence-based management of chronic cough.

Isolated IgG4 related disease of the trachea.

IgG4 related disease (IgG4-RD) is a multisystem inflammatory disease and can affect several organs including salivary glands, orbits, lungs, pancreas, kidneys and lymph nodes. Up to 40 % of patients have allergic manifestations including asthma, chronic rhinosinusitis, eczema and asthma. Commonly pulmonary manifestations include pulmonary nodules ranging from <1 to 5 cm in diameter, interstitial opacities and mediastinal lymphadenopathy. Rarely, IgG4-RD presents as isolated tracheal disease. Symptoms include dyspnea and stridor due to airway narrowing. Diagnosis of IgG4-RD including tracheal IgG4-RD requires a biopsy. The histologic specimen is characterized by lymphoplasmacytic infiltrate with high density of IgG4 positive plasma cells, and storiform fibrosis (a cartwheel appearance of fibroblasts and inflammatory cells). Up to 30 % of patients with IgG4-RD have normal serum IgG4 levels. The mainstay of therapy is glucocorticoids for those with systemic disease. Rituximab is an alternative for those who cannot tolerate glucocorticoids or those with disease recurrence. Patients with tracheal disease often require balloon dilation. Recurrence is common in patients and up to two thirds of patients have residual disease despite treatment. These patients often require surgical resection of affected area for symptomatic relief.

Association of pruritus and chronic cough: an all of us database study.

PURPOSE: Based on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions. MATERIALS AND METHODS: A nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables. RESULTS: CC patients (n = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients (n = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls. CONCLUSIONS: These results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study's insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.

Post-traumatic pseudoaneurysm of the descending aorta.

High-energy deceleration injuries of the thoracic aorta are associated with high mortality. But among long term survivors, just 2 %-5 % of traumatic aortic injuries fail initial detection and are discovered later (Pozek et al., 2012 [1]). We present a rare case of pseudoaneurysm of the descending aorta in a female with a history of chest blunt trauma 45 days before who presented with chronic severe cough and vocal hoarseness that was treated with endovascular intervention in our center.

Positive effect of deep diaphragmatic breathing training on gastroesophageal reflux-induced chronic cough: a clinical randomized controlled study.

BACKGROUND AND OBJECTIVE: To explore the efficacy of deep diaphragmatic breathing training (DEP) in patients with gastroesophageal reflux-induced chronic cough (GERC). METHODS: A randomized controlled study was conducted involving 60 GERC patients who were divided into the intervention group and the control group (each with 30 patients). Both groups received routine medication treatment for GERC, while the intervention group received DEP training additionally. Both groups were evaluated by cough symptom scores, Hull airway reflux questionnaire (HARQ), gastroesophageal reflux diagnostic questionnaire (GerdQ), generalized anxiety disorder scale-7 (GAD-7), patient health questionnaire-9 (PHQ-9), Pittsburgh sleep quality index (PSQI), the Leicester cough questionnaire (LCQ), as well as capsaicin cough sensitivity testing, B-ultrasound and surface electromyography (sEMG) of the diaphragmatic muscles before and after treatment. The cough resolution rate and changes of the above indictors was compared between the two groups after eight weeks of treatment. RESULTS: After eight weeks of treatment, cough symptoms improved in both groups, but the cough resolution rate in the intervention group of 94% was significantly higher than that in the control group of 77% (χ2 = 6.402, P = 0.041). The intervention group showed significant improvements to the control group in GerdQ (6.13(0.35) VS 6.57(0.77)), GAD-7 (0(0;1) VS 1(0;3)), PSQI (2(1;3) VS 4(3;6)), LCQ (17.19(1.56) VS 15.88(1.92)) and PHQ-9 (0(0;0) VS 0(0;3)) after treatment. Compared to control group, sEMG activity of the diaphragmatic muscle was significantly increased in the intervention group after treatment, measured during DEP (79.00(2.49) VS 74.65 (1.93)) and quiet breathing (72.73 (1.96) VS 67.15 (2.48)). CONCLUSION: DEP training can improve cough symptoms as an adjunctive treatment in GERC patients. TRIAL REGISTRATION: The protocol was registered in February 2, 2022 via the Chinese Clinical Trials Register ( http://www.chictr.org.cn/ ) [ChiCTR2200056246].

Single- and Multiple-Dose Pharmacokinetics of Gefapixant (MK-7264), a P2X3 Receptor Antagonist, in Healthy Adults.

Gefapixant (MK-7264, RO4926219, AF-219) is a first-in-class P2X3 antagonists being developed to treat refractory or unexplained chronic cough. The initial single- and multiple-dose safety, tolerability, and pharmacokinetics of gefapixant at doses ranging from 7.5 to 1800 mg were assessed in four clinical trials. Following single-dose administration of 10-450 mg, the pharmacokinetic (PK) profile of gefapixant in plasma and urine demonstrated low inter-subject variability and a dose-proportional exposure. Following administration of multiple doses twice daily, the plasma exposures were dose-proportional at doses ranging from 7.5 to 50 mg and less than dose-proportional at doses ranging from 100 to 1800 mg. The time to mean peak drug concentration ranged from 2 to 3 h post-dose, and steady state was achieved by 7 days after dosing, with an accumulation ratio of approximately 2, comparing data from day 1 to steady state. The mean apparent terminal half-life ranged from 8.2 to 9.6 h. Gefapixant was primarily excreted unmodified in urine. Gefapixant was well tolerated following single-dose administration up to 1800 mg and multiple doses up to 1800 mg twice daily; there were no serious adverse events (AEs) reported. The most common AE reported was dysgeusia. The PK profile supports a twice-daily dosing regimen.

Rasch validation of the short form (8 item) PC-QoL questionnaire and applicability of use as a health state classification system for a new preference-based measure.

BACKGROUND: The parent-proxy paediatric chronic cough quality of life questionnaire (PC-QoL) is a commonly used measure of spillover quality of life in parents of children with chronic cough. To date, spillover health utility in these parents is not routinely estimated largely due to the lack of a suitable instrument. Their perspective is not included in economic evaluations of interventions for their children. We explored developing a health state classification system based on the PC-QoL for measuring health utility spill over in this population. METHODS: This study included PC-QoL 8-item responses of 653 parents participating in a prospective cohort study about paediatric chronic cough. Exploratory factor analysis (EFA) and Rasch analysis were used to examine dimensionality and select potential items and level structure. RESULTS: EFA indicated that the PC-QoL had one underlying domain. Rasch analysis indicated threshold disordering in all items which improved when items were collapsed from seven to four levels. Two demonstrated differential item functioning (DIF) by diagnosis or ethnicity and were excluded from the final scale. This scale satisfied Rasch assumptions of local independence and unidimensionality and demonstrated acceptable fit to the Rasch model. It was presented to and modified by an expert panel and a consumer panel. The resulting classification system had six items, each with four levels. DISCUSSION: The PC-QoL can conform to a Rasch model with minor modifications. It may be a good basis for the classification system of a child cough-specific PBM. A valuation study is required to estimate preference weights for each item and to estimate health utility in parents of children with chronic cough.

[Syndromic approach in migrant patients: Fever, diarrhea, anemia, eosinophilia and chronic cough]. / Abordaje sindrómico en el paciente inmigrante: fiebre, diarrea, anemia, eosinofilia y tos crónica.

Migrant patients share the same diseases as natives, but biological or environmental differences may lead to distinct prevalence and manifestations of certain syndromes. Some common conditions in Primary Care stand out, such as fever, diarrhea, anemia, eosinophilia, and chronic cough, where it is important to have a special consideration. Fever may indicate a serious imported illness, and malaria should always be ruled out. Diarrhea is generally of infectious origin, and in most cases, management is outpatient. Anemia may indicate malnutrition or malabsorption, while eosinophilia may indicate a parasitic infection. Lastly, chronic cough may be a sign of tuberculosis, especially in immigrants from endemic areas. Family medicine holds a privileged position for the comprehensive, culturally sensitive, and person-centered approach to these conditions.

Noninvasive Bolus Transit Detection in Cervical Esophagus Utilizing Ultrasound Characteristics.

This pilot study aims to identify characteristic A-mode ultrasound features relevant to noninvasive detection of esophageal bolus transit in the proximal esophagus. Ultrasound signals at a lateral neck site were obtained via a single-element ultrasonic transducer with synchronous videofluoroscopic swallowing studies images of swallows of differing viscosities in 21 adult dysphagia outpatients. Characteristic ultrasound features were extracted to differentiate a bolus-filled from a collapsed esophagus. From 21 subjects, 412 swallows exhibited 4 reproducible waveform patterns associated with bolus transit as displayed in a heatmap: (1) Strong Reflectors; (2) Echo Shifts; (3) Distal Acoustic Enhancement; and (4) Speckling: One or more of these features were observed in the swallow series for all 21 subjects. Distinct acoustic waveform features acquired by single-element ultrasonic transducers can identify bolus transit through the cervical esophagus.

Chronic Bronchitis in Children and Adults: Definitions, Pathophysiology, Prevalence, Risk Factors, and Consequences.

The complex nature of chronic bronchitis (CB) and changing definitions have contributed to challenges in understanding its aetiology and burden. In children, CB is characterised by persistent airway inflammation often linked to bacterial infections and is therefore termed "protracted bacterial bronchitis" (PBB). Longitudinal studies suggest that CB in childhood persists into adulthood in a subgroup. It can also be associated with future chronic respiratory diseases including asthma, bronchiectasis, and chronic obstructive pulmonary disease (COPD). Adult CB is traditionally associated with smoking, occupational exposures, and lower socioeconomic status. The interplay between risk factors, childhood CB, adult CB, and other chronic respiratory diseases is intricate, requiring comprehensive longitudinal studies for a clearer understanding of the natural history of CB across the lifespan. Such longitudinal studies have been scarce to date given the logistic challenges of maintaining them over time. In this review, we summarise current evidence on the evolution of the definitions, pathophysiology, risk factors, and consequences of childhood and adulthood chronic bronchitis.

Development of an Italian version of the Leicester cough questionnaire and its relationship with other symptom-specific measures for patients with chronic cough.

OBJECTIVE: To implement subjective methods for measuring the impact of chronic cough on patients' daily life, including an Italian version of the symptom-specific, health status measure for patients with chronic cough, i.e. the Leicester Cough Questionnaire (LCQ). METHODS: Sixty-five chronic cough patients attended a tertiary cough clinic on two separate occasions 8 weeks apart. The visual analogue scale for cough severity (VAS), the LCQ and the cough disturbance score (CDS) were administered on both occasions. The LCQ was adapted for Italian conditions following a forward-backward translation procedure. Concurrent validation, internal consistency, repeatability and responsiveness were determined. RESULTS: The CDS, VAS and LCQ were correlated (r coefficients ranging from 0.69 to 0.94, p < 0.01). The internal consistency for each LCQ domain was high (alpha coefficient range 0.87-0.93), as was the 8-week repeatability of the LCQ in the patients (n = 36, 60 %) who displayed no change in CDS and VAS (intra-class correlation coefficient = 0.86, p < 001) over the same period. Patients who reported an improvement in CDS and VAS after 8 weeks (n = 29) also demonstrated significant improvements in each LCQ domain. The mean difference in LCQ total score before and after improvements was 2.26 (95 % CI: 1.58-4.47). CONCLUSIONS: The Italian version of the LCQ appears to be just as valid as the other language versions of the questionnaire. In addition, the CDS appears to be a clinically useful, symptom-specific measure of the overall disturbance provoked by cough.

Does diet quality moderate the long-term effects of discrete but extreme PM2.5 exposure on respiratory symptoms? A study of the Hazelwood coalmine fire.

In 2014, a fire at an open cut coalmine in regional Victoria, Australia burned for 6 weeks. Residents of the nearby town of Morwell were exposed to smoke, which included high levels of fine particulate matter (PM2.5). We investigated whether the long-term effects of PM2.5 on respiratory health were moderated by diet quality. A cross-sectional analysis was conducted of data collected 8.5 years after the mine fire from 282 residents of Morwell and 166 residents from the nearby unexposed town of Sale. Primary outcomes were respiratory symptoms. Exposure was coalmine fire-related PM2.5 and diet quality was assessed as Australian Recommended Food Score (ARFS) derived using the Australian Eating Survey (AES). The moderating effect of diet quality on respiratory outcomes associated with PM2.5 was assessed using logistic regression models, adjusting for potential confounders. Diet quality was poor in this sample, with 60% in the lowest category of overall diet quality. Overall diet quality and fruit and vegetable quality significantly attenuated the association between PM2.5 and prevalence of chronic cough and phlegm. Sauce/condiment intake was associated with a greater effect of PM2.5 on COPD prevalence. No other moderating effects were significant. The moderating effects of overall diet quality and vegetable and fruit intake aligned with a priori hypotheses, suggesting potential protective benefits. While more evidence is needed to confirm these findings, improving diets, especially fruit and vegetable intake, may provide some protection against the effects of smoke exposure from fire events.